Azabicyclic compounds as inhibitors of monoamines reuptake

ABSTRACT

The present invention relates to novel compounds of formula (I)′, and pharmaceutically acceptable salts, prodrugs or solvates thereof: 
     
       
         
         
             
             
         
       
     
     wherein
     R 1  is hydrogen or C 1-4  alkyl;   R 2  is a group A, K or W
 
wherein
   A is   

     
       
         
         
             
             
         
       
         
         K is an α or β naphthyl group, optionally substituted by 1 or 2 groups R 18 , each of them being the same or different;
 
and
 
         W is 
       
    
     
       
         
         
             
             
         
       
     
     and wherein
     G is a 5,6-membered monocyclic heteroaryl group, or a 8- to 11-membered heteroaryl bicyclic group; wherein G may be substituted by (R 15 ) p , which can be the same or different;   p is an integer from 0 to 5;   R 3  is selected from the group consisting of: hydrogen, fluorine, and C 1-4  alkyl; or corresponds to a group X or X 1 ;   R 4  is selected from the group consisting of: hydrogen, fluorine, and C 1-4  alkyl; or corresponds to a group X or X 1 ;   R 5  is hydrogen or C 1-4  alkyl;   R 7  is hydrogen or C 1-4  alkyl; or is a group X, X 1 , X 2  or X 3 ;
 
wherein
   X is   

     
       
         
         
             
             
         
       
         
         X 1  is 
       
    
     
       
         
         
             
             
         
       
         
         X 2  is 
       
    
     
       
         
         
             
             
         
       
     
     and
     X 3  is   

     
       
         
         
             
             
         
       
         
         R 6  is hydrogen or C 1-4  alkyl; or is a group X or X 1 ; 
         R 9  is C 1-4 alkyl; 
         R 10  is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl and SF 5 ; or corresponds to a group R 8 ; 
         R 8  is a 5-6 membered heterocycle group, which may be substituted by one or two substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkanoyl; 
         R 11  is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl and SF 5 ; or corresponds to a group R 8 ; 
         R 12  is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl and SF 5 ; or corresponds to a group R 8 ; 
         R 13  is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl and SF 5 ; or corresponds to a group R 8 ; 
         R 14  is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl and SF 5 ; or corresponds to a group R 8 ; 
         R 15  is selected from the group consisting of: halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl and SF 5 ; or corresponds to a group R 8 ; 
         R 16  is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkylC 1-3 alkyl; 
         R 17  is hydrogen or C 1-4 alkyl; 
         R 18  is selected from the group consisting of: halogen, cyano, and C 1-4 alkyl; 
         R 19  is haloC 1-2 alkyl; and 
         n is 1 or 2; 
         with the proviso that: 
         if R 2  is A, R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 13 , and R 14  are hydrogen, and R 12  is fluorine, R 1  is C 1-4 alkyl;    
         if R 2  is A, R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 13 , and R 14  are hydrogen, and R 1  is methyl, R 12  is halogen, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 1-4 alkanoyl or SF 5 ; or corresponds to a group R 8 ;
 
and processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as serotonin (5-HT), dopamine (DA) and norepinephrine (NE), re-uptake inhibitors.

The present invention relates to novel compounds, processes for theirpreparation, intermediates used in these processes, pharmaceuticalcompositions containing them and their use in therapy, as serotonin(5-HT), dopamine (DA) and norepinephrine (NE), re-uptake inhibitors.

Brain tissue is constituted of neuronal cells which are able tocommunicate with each other via specific cellular structures namedsynapses. The exchange of signals between neurons in the synapseshappens through neurochemical messengers named neurotransmitters, actingon specific target protein molecules, both post and pre-synaptic,referred to as receptors. Monoamines represent a family of smallneurotransmitter molecules sharing common chemical features, and includeserotonin (5-HT), dopamine (DA) and norepinephrine (NE).

Monoamine neurotransmitters are released into the synaptic cleft betweenneurons and interact with receptors present on the membrane of thetarget cells. The switch of the neurochemical signal occurs mainly byremoval of the neurotransmitter molecules through other proteinmolecules referred to as monoamine transporters (SERT for 5-HT, DAT forDA and NET for NE). Transporters are able to bind neurotransmittermolecules and move them into the presynaptic terminals, this cellularmechanism referred to as re-uptake. Pharmacological inhibition of there-uptake process can cause an increase of monoamine at synaptic leveland as a consequence an enhancement of the physiological activity ofneurotransmitters.

Serotonergic neurotransmission in the brain is mediated by a largefamily of receptors comprising both the G-protein coupled receptors andligand-gated ion channels including 14 subtypes, and is involved in avast variety of physiologic functions.

Compounds endowed of inhibitory properties at the SERT are predicted tohave the ability to treat in mammals, including humans, a variety ofdisorders associated with this neural system, for example eatingdisorders, major depression and mood disorders, obsessive compulsivedisorders, panic disorders, alcoholism, pain, memory deficits andanxiety. Included among these disorders are disorders related todepression, such as pseudodementia or Ganser's syndrome, migraine pain,bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome,tobacco abuse, panic disorder, post-traumatic syndrome, memory loss,dementia of ageing, acquired immunodeficiency syndrome dementia complex,memory dysfunction in ageing, social phobia, attention deficithyperactivity disorder, chronic fatigue syndrome, premature ejaculation,erectile difficulty, anorexia nervosa, disorders of sleep, autism,mutism or trichotillomania.

Major depression is an affective disorder, or disorder of mood,characterized by several symptoms including feeling of profound sadness,worthlessness, despair and loss of interest in all pleasures(anhedonia), recurrent thoughts of death, mental slowing, loss ofenergy, an inability to take decision, often associated with anxiety andagitation. These symptoms are persistent and can range from mild tosevere.

The pathophysiology of major depression is poorly understood being amultifactorial syndrome and, due to this, several neurotransmittersystems have been implicated. However, it is generally believed that thedisorder stems from a decrease in the synaptic concentration ofmonoamine neurotransmitters, mainly NE and 5-HT, in critical brainareas, leading to the “monoamine theory” of depression.

Several lines of preclinical and clinical evidence indicate that anenhancement of serotonin-mediated neurotransmission might be effectivein the treatment of major depression and actually the selectiveserotonin re-uptake inhibitors (SSRIs) have come to dominate the therapyof depression over the last two decades. Fluoxetine, the first SSRI tobe introduced, is the prototype of this group. Other members includeParoxetine, Sertraline, Fluvoxamine, Citalopram.

However, it is not clear exactly how these agents act to relievedepression. As with other classes of antidepressant, there is a lag ofseveral weeks before the onset of the mood-elevating effect, despite therapid blockade of the serotonin re-uptake. It is presumed that secondaryadaptive changes must occur at serotonergic synapses after chronicadministration of SSRIs i.e. down-regulation of release-regulatingautoreceptors and increased neurotransmitter release. The delayed onsetof anti-depressant effect is considered to be a serious drawback tocurrently used SSRIs. Moreover, although there is generally goodtolerability of SSRIs, the elevation of 5-HT levels at central andperipheral synapses leads to stimulation of receptor subtypes like5-HT_(2c) and 5-HT₃, which contributes to agitation and restless, alongwith gastrointestinal and sexual side-effects.

The success of the SSRIs rekindled interest in the development ofselective norepinephrine re-uptake inhibitors (SNRIs) as potentialantidepressants. A number of such compounds have been synthesized, e.g.Nisoxetine, Maprotiline, Tomoxetine and Reboxetine. Furthermore, manycompounds, including old tricyclic antidepressants, have a mixed NET andSERT inhibition profile, like. Imipramine and Amitriptyline (with SERTpotency>NET) and Desipramine, Nortriptyline, and Protriptyline (NETpotency>SERT).

The pharmacological manipulation of the DAT can in principle have theability to elevate DA levels in the mesolimbic system, reversing theanhedonia that is a core symptom of major depression. A DAT inhibitioncomponent, in combination with a blockade of SERT and NET, can also havethe ability to improve the lack of motivation and attention and enhancecognitive deficits seen in depressed patients. On the other hand,blockade of DAT has to be carefully managed in order to avoid potentialreinforcing effects and abuse liability. However compounds with DATinhibition in their pharmacology, such as Dexmethylphenidate,Methylphenidate and Bupropion, have been successfully marketed. Clinicalstudies indicate that patients with poor response to SSRIs benefit fromcombination therapy with agents that enhance dopaminergic tone. As aresult, compounds with a strong SERT inhibiting activity combined with awell balanced NET blockade and moderate DAT inhibiting activity maytherefore provide a replacement for current combination therapies fortreating unresponsive patients, providing greater efficacy andtherapeutic flexibility with a more rapid onset of anti-depressanteffect.

Due to their valuable DAT inhibition, the compounds of the presentinvention are considered useful for the treatment of Parkinsonism,depression, obesity, narcolepsy, drug addiction or misuse, includingcocaine abuse, attention-deficit hyperactivity disorders, Gilles de laTourettes disease and senile dementia. Dopamine re-uptake inhibitorsenhance indirectly via the dopamine neurones the release ofacetylcholine and are therefore also useful for the treatment of memorydeficits, e.g. in Alzheimers disease, presenile dementia, memorydysfunction in ageing, and chronic fatigue syndrome. Noradrenalinere-uptake inhibitors are considered useful for enhancing attention,alertness, arousal, vigilance and for treating depression.

One object of the present invention is to provide novel pharmaceuticalcompositions comprising compounds which are serotonin (5-HT), dopamine(DA) and norepinephrine (NE) re-uptake inhibitors.

Furthermore, the object of the present invention is to provide novelcompounds which are serotonin (5-HT), dopamine (DA) and norepinephrine(NE) re-uptake inhibitors.

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (A) or a pharmaceuticallyacceptable salt, solvate or prodrug thereof:

whereinR₁ is hydrogen or C₁₋₄alkyl;R₂ is a group A, K or Wwherein

A is

K is an α or β naphthyl group, optionally substituted by 1 or 2 groupsR₁₈, each of them being the same or different;and

W is

and whereinG is a 5,6-membered monocyclic heteroaryl, or a 8- to 11-memberedheteroaryl bicyclic group; such G may be substituted by (R₁₅)_(p), whichcan be the same or different;p is an integer from 0 to 5;R₃ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₄ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₅ is hydrogen or C₁₋₄ alkyl;R₇ is hydrogen or C₁₋₄ alkyl; or is a group X, X₁, X₂ or X₃;wherein

X is

X₃ is

X₂ is

and

X₃ is

R₈ is hydrogen or C₁₋₄ alkyl; or is a group X or X₁;R₉ is C₁₋₄alkyl;R₁₀ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₈ is a 5-6 membered heterocycle group, which may be optionallysubstituted by one or two substituents selected from a group consistingof: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy andC₁₋₄alkanoyl;R₁₁ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;

-   R₁₂ is selected from a group consisting of: hydrogen, halogen,    hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,    haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;-   R₁₃ is selected from a group consisting of: hydrogen, halogen,    hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,    haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;-   R₁₄ is selected from a group consisting of: hydrogen, halogen,    hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,    haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;-   R₁₅ is selected from a group consisting of: halogen, hydroxy, cyano,    C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl    and SF₅; or corresponds to a group R₈;-   R₁₆ is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or    C₃₋₆cycloalkylC₁₋₃alkyl;-   R₁₇ is hydrogen or C₁₋₄alkyl;-   R₁₈ is selected from a group consisting of: halogen, cyano,    C₁₋₄alkyl;-   R₁₉ is haloC₁₋₂alkyl;-   n is 1 or 2;    and a pharmaceutically acceptable carrier.

Compound 6-(4-fluorophenyl)-3-azabicyclo[4.1.0]heptane shown below

has been disclosed in the patent application No WO2004072025(“Preparation of N-aryl heterocycles as melanin concentrating hormone(MCH) antagonists”) wherein it has been used as an intermediate forsynthesis of final compounds. No therapeutic use has been indicated forthis compound in the patent application.

Compound 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane shown below

has been disclosed in the publication titled “A Novel and SelectiveMonoamine Oxidase B substrate” Rimoldi, J. et al., Bioorganic andMedicinal Chemistry (2005), 13 (20), 5808-5813. Nonetheless, notherapeutic use has been indicated for this compound.

In another aspect, the invention provides a method for the treatment ofa mammal, including man, in particular for the treatment of disorders ordiseases responsive to the serotonin (5-HT), dopamine (DA) andnorepinephrine (NE), re-uptake inhibiting activity of the compounds,comprising administration of an effective amount of a compound offormula (A) as above defined or a pharmaceutically acceptable salt,solvate or prodrug thereof.

In one embodiment, the invention provides a method of treating acondition for which inhibition of serotonin (5-HT), dopamine (DA) andnorepinephrine (NE), is beneficial, which comprises administering to amammal (e.g. human) in need thereof an effective amount of a compound offormula (A) as above defined or a pharmaceutically acceptable salt,solvate or prodrug thereof.

In a further aspect, the invention provides a compound of formula (A) asabove defined or a pharmaceutically acceptable salt, solvate or prodrugthereof for use in therapy.

In one embodiment, the invention provides a compound of formula (A) asabove defined or a pharmaceutically acceptable salt, solvate or prodrugthereof, for use in the treatment of a condition in a mammal for whichinhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) isbeneficial.

In a still further aspect, the invention provides the use of a compoundof formula (A) as above defined or a pharmaceutically acceptable salt,solvate or prodrug thereof, for the manufacture of a medicament for thetreatment of disorders or diseases responsive to the serotonin (5-HT),dopamine (DA) and norepinephrine (NE), re-uptake inhibiting activity.

In one embodiment, the invention provides the use of a compound offormula (A) as above defined or a pharmaceutically acceptable salt,solvate or prodrug thereof in the manufacture of a medicament for thetreatment of a condition in a mammal for which inhibition of serotonin(5-HT), dopamine (DA) and norepinephrine (NE) is beneficial.

In one aspect, the present invention provides a compound of formula (I)or a pharmaceutically acceptable salt, solvate or prodrug thereof:

whereinR₁ is hydrogen or C₁₋₄ alkyl;R₂ is a group A, K or Wwherein

A is

K is an α or β naphthyl group, optionally substituted by 1 or 2 groupsR₁₈, each of them being the same or different;and

W is

and whereinG is a 5,6-membered monocyclic heteroaryl, or a 8- to 11-memberedheteroaryl bicyclic group; such G may be substituted by (R₁₅)_(p), whichcan be the same or different;p is an integer from 0 to 5;R₃ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₄ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₅ is hydrogen or C₁₋₄alkyl;R₇ is hydrogen or C₁₋₄ alkyl; or is a group X, X₁, X₂ or X₃;wherein

X is

X₁ is

X₂ is

and

X₃ is

R₆ is hydrogen or C₁₋₄alkyl; or is a group X or X₁;R₉ is C₁₋₄alkyl;R₁₀ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₅;R₅ is a 5-6 membered heterocycle group, which may be optionallysubstituted by one or two substituents selected from a group consistingof: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy andC₁₋₄alkanoyl;R₁₁, is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₁₂;R₁₂ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₃ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₄ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₅ is selected from a group consisting of: halogen, hydroxy, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andSF₅; or corresponds to a group R₈;R₁₆ is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₃alkyl;R₁₇ is hydrogen or C₁₋₄alkyl;R₁₈ is selected from a group consisting of: halogen, cyano, C₁₋₄alkyl;R₁₉ is haloC₁₋₂alkyl;n is 1 or 2;with the proviso that:if R₂ is A, R₃, R₄, R₅, R₆, R₇, R₁₀, R₁₁, R₁₃, R₁₄ are hydrogen, and R₁₂is fluorine, R₁₂ is C₁₋₄ alkyl;if R₂ is A, R₃, R₄, R₅, R₆, R₇, R₁₀, R₁₁, R₁₃, R₁₄ are hydrogen, and R₁is methyl, R₁₂ is halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to agroup R₈.

In another aspect, the present invention provides a compound of formula(IF) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

whereinR₁ is hydrogen or C₁₋₄alkyl;R₂ is a group A or Wwherein

A is

and

W is

and whereinG is a 5,6-membered monocyclic heteroaryl, or a 8- to 11-memberedheteroaryl bicyclic group; such G may be substituted by (R₁₅)_(p), whichcan be the same or different;p is an integer from 0 to 5;R₃ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₄ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₅ is hydrogen or C₁₋₄ alkyl;R₁ is hydrogen or C₁₋₄alkyl; or is a group X or X₁ wherein

X is

X₁ is

X₂ is

and

X₃ is

and whereinR₇ is hydrogen or C₁₋₄ alkyl; or is a group X, X₁, X₂ or X₃;R₈ is a 5-6 membered heterocycle group, which may be substituted by oneor two substituents selected from a group consisting of: halogen, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;R₉ is C₁₋₄alkylR₁₀ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₁ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₂ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₃ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₄ is selected from a group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈;R₁₅ is selected from a group consisting of: halogen, hydroxy, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andSF₅; or corresponds to a group R₈;R₁₆ is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₃alkyl;n is 1 or 2;with the proviso that:if one group of R₁₁ or R₁₃ is not hydrogen, at least one group of R₁₀,R₁₂ or R₁₄ is not hydrogen;if R₂ is A, R₃, R₄, R₅, R₆, R₇, R₁₀, R₁₁, R₁₃, R₁₄ are hydrogen, and R₁₂is fluorine, R₁ is not hydrogen;if R₂ is A, R₃, R₄, R₅, R₆, R₇, R₁₀, R₁₁, R₁₃, R₁₄ are hydrogen, and R₁is methyl, R₁₂ is not hydrogen.

In a further aspect, the present invention provides a compound offormula (IG) or a pharmaceutically acceptable salt, solvate or prodrugthereof:

whereinR₁ is hydrogen or C₁₋₄ alkyl;

R₂ is

p is an integer from 0 to 5;R₃ is selected in the group consisting of: hydrogen, fluorine, and C₁₋₄alkyl; or corresponds to a group X or X₁;R₄ is selected in the group consisting of: hydrogen, fluorine, andC₁₋₄alkyl; or corresponds to a group X or X₁;R₅ is hydrogen or C₁₋₄ alkyl;R₆ is hydrogen or C₁₋₄alkyl; or is a group X or X₁wherein

X is

X₁ is

X₂ is

and

X₃ is

and whereinR₇ is hydrogen or C₁₋₄alkyl; or is a group X, X₁, X₂ or X₃;R₈ is a 5-6 membered heterocycle group, which may be substituted by oneor two substituents selected from a group consisting of: halogen, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl;R₉ is C₁₋₄alkylR₁₀ is selected from a group consisting of: halogen, hydroxy, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andSF₅; or corresponds to a group R₈;R₁₁ is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₄alkyl;n is 1 or 2.

Because of the presence of the fused cyclopropane ring, compounds offormula (I) are believed to have a “cis” disposition of the substituents(both groups R₂ and R₇ linked to the bicyclic ring system are on thesame face of this bicyclic ring system).

It will be appreciated that compounds of formula (I) possess at leasttwo stereogenic centers, namely at position 1 and 6 in the3-azabicyclo[4.1.0]heptane portion of the molecule. Thus, the compoundsmay exist in two stereoisomers which are enantiomers with respect to thestereogenic centers in the cyclopropane ring. It will also beappreciated, in common with most biologically active molecules that thelevel of biological activity may vary between the individualstereoisomers of a given molecule. It is intended that the scope of theinvention includes all individual stereoisomers (diastereoisomers andenantiomers) and all mixtures thereof, including but not limited toracemic mixtures, which demonstrate appropriate biological activity withreference to the procedures described herein.

In one embodiment of the present invention compounds of formula (I)′ areprovided which correspond to the compounds of formula (I), orpharmaceutically acceptable salts, solvates or prodrugs thereof, having“cis” disposition, represented by the bold highlight of the two bondsnear the cyclopropyl moiety:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₇ are defined as above forcompounds of formula (I).

From now on throughout the document, the symbol ′ (prime) is used toidentify compounds having “cis” disposition for the bonds bearing groupsR₂ and R₇, represented by the bold highlight of the two bonds near thecyclopropyl moiety.

In one embodiment of the present invention, the bold highlight of thetwo bonds near the cyclopropyl moiety bearing groups R₂ and R₇,indicate, mixtures (including but not limited to racemic mixtures) ofthose cis isomers.

In compounds of formula (I)′ there are at least two stereogenic centers,which are located in the cyclopropane portion, as depicted below;through optical resolution of a mixture containing the two stereoisomerswhich are enantiomers with respect to the stereogenic centers atpositions named 1 and 6, steroisomers of compounds of formula (I)′having a single absolute configuration at stereogenic centers named 1and 6, may be obtained as shown in the scheme below:

Absolute configuration of stereogenic centers at position named 1 and 6may be assigned using Cahn-Ingold-Prelog nomenclature based on groups'priorities.

In another embodiment of the present invention compounds of formula (I)″are provided which correspond to the compounds of formula (I), orpharmaceutically acceptable salts, solvates or prodrugs thereof, asstereochemical isomers having a “cis” disposition for bonds bearinggroups R₂ and R₇, and a single but unknown configuration at stereogeniccenters named 1 and 6:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₇ are defined as above forcompounds of formula (I).

In the context of the present invention, the representation shown abovein compounds of formula (I)″ for the two bonds near the cyclopropylmoiety bearing groups R₂ and R₇ indicate a cis stereoisomer, which has asingle but unknown absolute configuration at stereogenic centers named 1and 6.

It is intended in the context of the present invention thatstereochemical isomers of formula (I)″ are enriched in one configurationat centers named 1 and 6. In one embodiment, the isomers correspond toat least 90% e.e. (enantiomeric excess). In another embodiment theisomers correspond to at least 95% e.e. In another embodiment theisomers correspond to at least 99% e.e.

From now on throughout the document, the symbol ″ (double prime) is usedto identify stereochemical isomers of the compounds of the inventionhaving “cis” disposition for the two bonds near the cyclopropyl moietybearing groups R₂ and R₇ and indicated with the representation shownabove for compounds of formula (I)″, those stereoisomers having a singlebut unknown absolute configuration at stereogenic centers named 1 and 6.

The absolute configuration of the optical isomers of some compounds ofthe present invention was assigned using ab initio VCD (vibrationalcircular dichroism).

Chiral molecules exhibit vibrational circular dichroism (VCD).Vibrational circular dichroism (VCD) is the differential interaction ofa chiral molecule with left and right circularly polarized infraredradiation during vibrational excitation.

The VCD spectrum of a chiral molecule is dependent on itsthree-dimensional structure. Most importantly, the VCD spectrum of achiral molecule is a sensitive function of its absolute configurationand, in the case of flexible molecules, of its conformation. Inprinciple, therefore, VCD permits the determination of the structure ofa chiral molecule. VCD spectra were first measured in the 1970s.Subsequently, VCD instrumentation has developed enormously in spectralrange and in sensitivity. Currently, VCD spectra of liquids andsolutions can be measured over the majority of the fundamental infrared(IR) spectral range (v≧ 650 cm⁻¹) with high sensitivity at acceptableresolution (1-5 cm⁻¹) using both dispersive and Fourier Transform (FT)VCD instrumentation. Very recently, commercial FT VCD instrumentationhas become available, greatly enhancing the accessibility of VCDspectra.

The use of VCD as a reliable method for the determination of absoluteconfiguration of chiral molecules is now well established (see forexample Shah R D, et al., Curr Opin Drug Disc Dev 2001; 4:764-774;Freedman T B, et al., Helv Chim Acta 2002; 85:1160-1165; Dyatkin A B, etal. Chirality 2002; 14:215-219; Solladie′-Cavallo A, Balaz Met al.,Tetrahedron Assym 2001; 12:2605-2611; Nafie L A, et al. Circulardichroism, principles and applications, 2nd ed. New York: John Wiley &Sons; 2000. p 97-131; Nafie L A, et al. in: Yan B, Gremlish H-U,editors. Infrared and Raman spectroscopy of biological materials. NewYork: Marcel Dekker; 2001. p 15-54; Polavarapu P L, et al., J Anal Chem2000; 366:727-734; Stephens P J, et al., Chirality 2000; 12:172-179;Solladie'-Cavallo A, et al., Eur J Org Chem 2002: 1788-1796).

The method entails comparison of observed IR and VCD spectra withcalculations of the spectra for a specific configuration and providesinformation both on the absolute configuration and on the solutionconformation.

Given an experimental spectrum of a chiral molecule whose absoluteconfiguration and/or conformation are unknown and to be determined, thegeneral procedure is as follows: 1) all possible structures are defined;2) the spectra of these structures are predicted; and 3) predictedspectra are compared to the experimental spectrum. The correct structurewill give a spectrum in agreement with experiment; incorrect structureswill give spectra in disagreement with experiment.

VCD spectra are always measured simultaneously with vibrationalunpolarized absorption spectra (“infrared (IR) spectra”) and the twovibrational spectra together provide more information than does the VCDspectrum alone. In addition, vibrational unpolarized absorption spectraare automatically predicted simultaneously with VCD spectra.

For ab initio assignments, VCD and unpolarized IR spectra werecalculated using the Gaussian 98 software package.

In one embodiment of the present invention compounds of formula (IA) areprovided that correspond to stereochemical isomers of compounds offormula (I)′, having the configuration shown in the picture below atstereogenic centers at position named 1 and 6:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₇ are defined as above forcompounds of formula (I), or pharmaceutically acceptable salts, solvatesor prodrugs thereof.

It is intended in the context of the present invention thatstereochemical isomers of formula (IA) are enriched in one configurationat stereogenic centers named 1 and 6. In one embodiment, the isomerscorrespond in one embodiment to at least 90% e.e. (enantiomeric excess).In another embodiment the isomers correspond to at least 95% e.e. Inanother embodiment the isomers correspond to at least 99% e.e.

From now on throughout the document, the suffix “A” in brackets is usedto identify stereochemical isomers of compounds of the invention havingthe configuration shown above for compounds of formula (IA) atstereogenic centers at positions named 1 and 6.

In another embodiment of the present invention compounds of formula (IB)are provided that correspond to stereochemical isomers of compounds offormula (I)′, having the configuration shown in the picture below atstereogenic centers at position named 1 and 6:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₁₇ are defined as above forcompounds of formula (I), or pharmaceutically acceptable salts, solvatesor prodrugs thereof.

It is intended in the context of the present invention thatstereochemical isomers of formula (IB) are enriched in one configurationat centers named 1 and 6. In one embodiment, the isomers correspond inone embodiment to at least 90% e.e. (enantiomeric excess). In anotherembodiment the isomers correspond to at least 95% e.e. In anotherembodiment the isomers correspond to at least 99% e.e.

From now on throughout the document, the suffix “B” in brackets is usedto identify stereochemical isomers of compounds of the invention havingthe configuration shown above for compounds of formula (IB) atstereogenic centers at positions named 1 and 6.

The term “C₁₋₄alkyl” refers to an alkyl group having from one to fourcarbon atoms, in all isomeric forms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

The term ‘C₃-C₆ cycloalkyl group’ as used herein means a non aromaticmonocyclic hydrocarbon ring of 3 to 6 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; while unsaturatedcycloalkyls include cyclopentenyl and cyclohexenyl, and the like.

The term ‘C₃₋₆cycloalkylC₁₋₃alkyl’ as used herein means an alkyl havingfrom one to three carbon atoms wherein one hydrogen atom is replacedwith a C₃-C₆ cycloalkyl group as above defined, for examplemethylcyclopropane.

The term “C₁₋₄alkoxy” refers to a linear chain or branched chain alkoxy(or “alkyloxy”) group having from one to four carbon atoms, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy andtert-butoxy.

The term ‘C₁₋₄ alkanoyl group’ as used herein may be a linear or abranched chain alkanoyl group, for example acetyl, ethylcarbonyl,n-propylcarbonyl, i-propyl carbonyl, n-butylcarbonyl or t-butylcarbonyland the like.

The term ‘halo C₁₋₄ alkyl’ as used herein means an alkyl group havingone or more carbon atoms and wherein at least one hydrogen atom isreplaced with halogen, preferably fluorine, such as for example atrifluoromethyl group and the like.

The term ‘halo C₁₋₄alkoxy group’ as used herein may be a C₁₋₄ alkoxygroup as defined before substituted with at least one halogen, such asOCH₂CF₃, OCHF₂, or OCF₃.

The term ‘halo C₁₋₂ alkyl group’ as used herein may be a C₁₋₂ alkylgroup as defined before substituted with at least one halogen,preferably fluorine, such as —CH₂CF₃, —CHF₂, or —CF₃.

The term “SF₅” refers to pentafluorosulfanyl.

The term “halogen” and its abbreviation “halo” refer to fluorine (F),chlorine (Cl), bromine (Br) or iodine (I). Where the term “halo” is usedbefore another group, it indicates that the group is substituted by oneor more halogen atoms.

The term ‘5,6-membered monocyclic heteroaryl’ as used herein means anaromatic monocyclic heterocycle ring of 5 or 6 members and having atleast one heteroatom selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom.

Representative 5, 6 membered monocyclic heteroaryl groups include (butare not limited to): furyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl,isooxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl andtetrazolyl.

The term ‘8, 11-membered bicyclic heteroaryl’ as used herein means anaromatic bicyclic heterocycle ring of 8 to 11 members and having atleast one heteroatom selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom.

Representative 8, to 11 membered bicyclic heteroaryl groups include (butare not limited to): benzofuranyl, benzothiophenyl, indolyl, isoindolyl,azaindolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl,benzothiazolyl, quinazolinyl and phthalazinyl.

The term 5-6 membered heterocycle means a 5-6 monocyclic heterocyclicring which is either saturated, unsaturated or aromatic, and whichcontains from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms maybe optionally oxidized, and the nitrogen heteroatom may be optionallyquaternized. Heterocycles include heteroaryl groups as defined above.The heterocycle may be attached via any heteroatom or carbon atom. Thus,the term include (but is not limited to) morpholinyl, pyridinyl,pyrazinyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl, oxadiazolyl,oxazolyl, isoxazolyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

Any of these groups may be attached to the rest of the molecule at anysuitable position.

In one embodiment, R₁ is hydrogen or C₁₋₄alkyl (for example methyl). Inanother embodiment, R₁ is hydrogen.

In one embodiment, R₂ is a group A or K. In another embodiment, R₂ is agroup A. In a further embodiment, R₂ is a group K.

In one embodiment, the group K is a 0 naphthyl group.

In one embodiment, R₃ is hydrogen or a group X. In another embodiment,R₃ is hydrogen.

In a further embodiment, R₃ is a group X.

In one embodiment, R₄ is hydrogen.

In one embodiment, R₅ is hydrogen.

In one embodiment, R₆ is hydrogen.

In one embodiment, R₇ is hydrogen or a group X, X₁ or X₂. In anotherembodiment, R₇ is hydrogen. In a further embodiment, R₇ is a group X, X₁or X₂.

In one embodiment, R₇ is a group X.

In one embodiment, R₇ is a group X₁.

In one embodiment, R₇ is a group X₂.

In one embodiment, n is 1 or 2. In another embodiment, n is 1.

In one embodiment, R₁₆ is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl orC₃₋₆cycloalkylC₁₋₃alkyl. In another embodiment, R₁₆ is hydrogen orC₁₋₄alkyl. In a further embodiment, R₁₆ is hydrogen. In a still furtherembodiment, R₁₆ is C₁₋₄alkyl (for example methyl or ethyl).

In one embodiment, R₁₇ is hydrogen or C₁₋₄alkyl. In another embodiment,R₁₇ is hydrogen.

In a further embodiment, R₁₇ is C₁₋₄alkyl (for example methyl).

In one embodiment, R₁₈ is halogen. In another embodiment, R₁₈ ischlorine.

In one embodiment, R₁₀ is hydrogen.

In one embodiment, R₁₄ is hydrogen.

In one embodiment, R₁₀ is hydrogen.

In one embodiment, R₁₁ is hydrogen, halogen, haloC₁₋₄alkyl,haloC₁₋₄alkoxy. In another embodiment, R₁₁ is hydrogen, halogen (forexample chlorine) or haloC₁₋₄alkyl (for example trifluoromethyl). In afurther embodiment, R₁₁ is halogen (for example chlorine) orhaloC₁₋₄alkyl (for example trifluoromethyl). In a still furtherembodiment, R₁₁ is chlorine.

In one embodiment, R₁₂ is halogen, haloC₁₋₄alkyl, haloC₁₋₄alkoxy. Inanother embodiment,

R₁₂ is halogen (for example chlorine or fluorine), haloC₁₋₄alkyl (forexample trifluoromethyl) or haloC₁₋₄alkoxy (for exampletrifluoromethoxy). In still another embodiment, R₁₂ is chlorine.

In one embodiment, R₁₃ is hydrogen, halogen, haloC₁₋₄alkyl,haloC₁₋₄alkoxy. In another embodiment, R₁₃ is hydrogen.

In one embodiment, a compound of formula (IC) or a pharmaceuticallyacceptable salt, solvate or prodrug thereof is provided, wherein R₁, R₂,R₇ and R₁₇ are as defined for formula (I):

In Formula (IC), in one embodiment, R₁ is hydrogen or C₁₋₄ alkyl (forexample methyl), R₂ is a group A or K, R₇ is hydrogen or a group X, X₁or X₂ and R₁₇ is hydrogen or C₁₋₄alkyl.

In Formula (IC), in a further embodiment, R₁ is hydrogen, R₂ is a groupA or K, R₇ is hydrogen or a group X, X₁ or X₂ and R₁₇ is hydrogen.

In one embodiment, a compound of formula (ID) or a pharmaceuticallyacceptable salt, solvate or prodrug thereof is provided, wherein R₇ is agroup X and R₂, R₁₆ and n are as defined for formula (I):

In Formula (ID), in one embodiment, R₂ is a group A.

In Formula (ID), in another embodiment, R₂ is a group A, R₁₆ ishydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₃alkyl, R₁₀ ishydrogen, R₁₄ is hydrogen, R₁₁ is hydrogen, halogen, haloC₁₋₄alkyl orhaloC₁₋₄alkoxy, R₁₂ is halogen, haloC₁₋₄alkyl or haloC₁₋₄alkoxy, R₁₃ ishydrogen, halogen, haloC₁₋₄alkyl or haloC₁₋₄alkoxy and n is 1.

In Formula (ID), in one embodiment, R₂ is a group K.

In Formula (ID), in another embodiment, R₂ is a group K, which is anunsubstituted, naphtyl ring, R₁₆ is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkylor C₃₋₆cycloalkylC₁₋₃alkyl and n is 1.

In one embodiment, a compound of formula (IE) or a pharmaceuticallyacceptable salt, solvate or prodrug thereof is provided, wherein R₁, R₂,R₃ and R₁₇ are as defined for formula (I):

In Formula (IE), in one embodiment, R₁ is hydrogen, R₂ is a group A orK, R₃ is a group X or X₁ and R₁₇ is hydrogen or C₁₋₄alkyl.

In Formula (IE), in another embodiment, R₁ is hydrogen, R₂ is a group A,R₃ is a group X, R₁₇ is hydrogen, R₁₆ is hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₄alkyl, R₁₀ is hydrogen, R₁₄ ishydrogen, R₁₁ is hydrogen, halogen, haloC₁₋₄alkyl or haloC₁₋₄alkoxy, R₁₂is halogen, haloC₁₋₄alkyl or haloC₁₋₄alkoxy, R₁₃ is hydrogen, halogen,haloC₁₋₄alkyl or haloC₁₋₄alkoxy and n is 1.

In one embodiment, compounds of formula (IC), (ID) and (IE) as abovedefined, having a single but unknown configuration at stereogeniccenters at position named 1 and 6, are provided. Those compounds arenamed (IC)″, (ID)″ and (IE)″.

In another embodiment, compounds of formula (IC), (ID) and (IE) as abovedefined, having the configuration shown above for compounds of formula(IA) at stereogenic centers at position named 1 and 6, are provided.Those compounds are named (ICA), (IDA) and (IEA).

In a further embodiment, compounds of formula (IC), (ID) and (IE) asabove defined, having the configuration shown above for compounds offormula (IB) at stereogenic centers at position named 1 and 6, areprovided. Those compounds are named (ICB), (IDB) and (IEB).

In the context of the present invention all the aspects and embodimentsof the invention described for compounds of formula (I) are intended toapply also to compounds of formula (A).

For example, corresponding embodiments to those described for compoundsof formula (I) are also provided for compounds of formula (A) [i.e.compounds of formula (A)′, (A)″, (AA), (AB), (AC), (AD), (AE) etc.],pharmaceutically acceptable salts, solvates and prodrug thereof beingincluded in the present invention.

Certain groups/substituents included in the present invention may bepresent as isomers. The present invention includes within its scope allsuch isomers, including racemates, enantiomers, tautomers and mixturesthereof.

Certain groups in compounds of formula (I) or in intermediates used toprepare them, may exist in one or more tautomeric forms. The presentinvention includes within its scope all such tautomeric forms, includingmixtures.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base, quaternary ammonium salts and internally formed salts andalso includes pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts are particularly suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompounds. Such salts must clearly have a physiologically acceptableanion or cation.

Salts of compounds of formula (I) may be prepared through conventionalmethods and are included within the scope of the present invention.

Certain of the compounds of the invention may form acid or base additionsalts with one or more equivalents of the acid or of the base. Thepresent invention includes within its scope all possible stoichiometricand non-stoichiometric forms.

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

Suitably pharmaceutically acceptable salts of the compounds of thepresent invention include acid addition salts formed with inorganicacids such as hydrochloric, hydrobromic, hydroiodic, phosphoric,metaphosphoric, nitric and sulfuric acids, and with organic acids, suchas tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric,benzoic, naphtoic, formic, propionic, glycolic, gluconic, maleic,succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic,saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic,salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, pantothenic, stearic, sulfanilic, alginic, galacturonicand arylsulfonic, for example benzenesulfonic and p-toluenesulfonic,acids; base addition salts formed with alkali metals and alkaline earthmetals and organic bases such as N,N-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), lysine and procaine; and internally formed salts.Salts having a non-pharmaceutically acceptable anion or cation arewithin the scope of the invention as useful intermediates for thepreparation of pharmaceutically acceptable salts and/or for use innon-therapeutic, for example, in vitro, situations.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compounds of the invention arewithin the scope of the invention. The compounds of formula (I) mayreadily be isolated in association with solvent molecules bycrystallisation or evaporation of an appropriate solvent to give thecorresponding solvates.

In addition, prodrugs are also included within the context of thisinvention. As used herein, the term “prodrug” means a compound which isconverted within the body, e.g. by hydrolysis in the blood, into itsactive form that has medical effects. Pharmaceutically acceptableprodrugs are described in T. Higuchi and V. Stella, Prodrugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher,S. Ramon and H. Barbra “Improved oral drug delivery: solubilitylimitations overcome by the use of prodrugs”, Advanced Drug DeliveryReviews (1996) 19(2) 115-130.

Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a patient, cleaves toform the hydroxy, amine or sulfhydryl groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol, sulfhydryl and amine functionalgroups of the compounds of structure (I). Further, in the case of acarboxylic acid (—COOH), esters may be employed, such as methyl esters,ethyl esters, and the like. Esters may be active in their own rightand/or be hydrolysable under in vivo conditions in the human body.Suitable pharmaceutically acceptable in vivo hydrolysable ester groupsinclude those which break down readily in the human body to leave theparent acid or its salt.

Hereinafter, compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and prodrugs defined in any aspect of theinvention (except intermediate compounds in chemical processes) arereferred to as “compounds of the invention”.

Furthermore, some of the crystalline forms of the compounds of thepresent invention, may exist as polymorphs, which are included in thepresent invention.

Those skilled in the art will appreciate that in the preparation of thecompounds of the invention, it may be necessary and/or desirable toprotect one or more sensitive groups in the molecule to preventundesirable side reactions. Suitable protecting groups for use accordingto the present invention are well known to those skilled in the art andmay be used in a conventional manner. See, for example, “Protectivegroups in organic synthesis” by T. W. Greene and P. G. M. Wuts (JohnWiley & sons 1991) or “Protecting Groups” by P. J. Kocienski (GeorgThieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

The present invention also includes isotopically-labelled compounds,which are identical to those recited in formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁸Cl, ¹²³I and ¹²⁵I.

Compounds of the present invention and non-pharmaceutically acceptablesalts thereof that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention andnon-pharmaceutically acceptable salts thereof can generally be preparedby carrying out the procedures disclosed in the Schemes and/or in theExamples below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

In one embodiment, the compounds of the invention are selected from thelist consisting of:

-   (1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;-   (1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;    and pharmaceutically acceptable salts, solvates, or prodrugs    thereof.

In another embodiment, the compounds of the invention are selected fromthe list consisting of:

-   (1R,6S/1S,6R)-6-phenyl-3-azabicyclo[4.1.0]heptane;-   (1R,6S)-6-phenyl-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-phenyl-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-6-[4-(trifluoromethyl)phenyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-6-[3-(trifluoromethyl)phenyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-(3,4-dichlorophenyl)-3-(1-methylethyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;    and pharmaceutically acceptable salts, solvates, or prodrugs    thereof.

In another embodiment, the compounds of the invention are selected fromthe list consisting of:

-   (1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;    [(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;-   [(1S,6R or    1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;-   [(1R,6S or    1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;-   (1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;-   (1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;-   (1S,4R,6R/1R,4S,6S)-6-(3,4-dichlorophenyl)-4-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S or    1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R or    1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptane;-   (1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;-   (1R,6S or    1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;-   (1S,6R or    1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;-   (1S,6R/1R,6S)-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane;-   (1S,6R,7R/1R,6S,7S)-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;    and pharmaceutically acceptable salts, solvates, or prodrugs    thereof.

In a further embodiment, the compounds of the invention are selectedfrom the list consisting of:

-   (1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S or    1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R or    1R,6S)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R or    1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1R,6S or    1S,6R)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;    (1S 16R or    1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;    and pharmaceutically acceptable salts, solvates, or prodrugs    thereof.

In a still further embodiment, the compounds of the invention areselected from the list consisting of:

-   (1S,6RY6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R or    1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;    and pharmaceutically acceptable salts, solvates, or prodrugs    thereof.

In another embodiment, the compound of the invention is(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof.

In a further embodiment, the compound of the invention is (1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof.

In another embodiment, compound of the invention is:

-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane    hydrochloride;-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane    (2R,3R)-2,3-dihydroxybutanedioate (L-tartrate salt);-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane    butanedioate (Mono-Succinate salt);-   (1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane    phosphate;    or a solvate thereof.

The present invention also provides a process for preparing a compoundof formula (I) or a salt thereof as defined above.

Compounds of the invention may be prepared in a variety of ways. In thefollowing reaction schemes and hereafter, unless otherwise stated R₁ toR₁₉, A, K, W, G, p, X, X₁, X₂, X₃ and n are as for compounds of formula(I).

Throughout the specification, general formulae are designated by Romannumerals (I), (II), (III), (IV) etc. Subsets of these general formulaeare defined as (Ia), (Ib), (Ic) etc. . . . (IVa), (IVb), (IVc) etc.

Compounds of the invention may be prepared according to the followingsynthetic schemes.

Synthetic Schemes

Compounds of formula (Ib), i.e. compounds of formula (I) whereinR₁═C₁₋₄alkyl, R₇=a group X (wherein n=1 and R₁₅═C₁₋₄ alkyl orC₁₋₃alkylC₃₋₆cycloalkyl) may be obtained starting from compounds offormula (Ia) wherein R₁═H and R₁₆═C₁₋₄alkyl or C₁₋₃alkylC₃₋₆cycloalkyl,according to Scheme 1, following standard alkylation procedures, e.g.using a RY alkylating agent (R═C₁₋₄ alkyl, Y=halogen), such as CH₃₁, atrialkylamine, such as TEA, in DCM, at temperature between 0° C. androom temperature.

Alternatively, compounds of formula (Ib) may be obtained throughreductive amination using a suitable aldehyde RCHO(R═C₁₋₃ alkyl), areducing agent such as NaCNBH₃. in aprotic or protic solvent (e.g.Toluene, THF or MeOH), at temperature between 80° C. and roomtemperature.

Compounds of formula (Ia), i.e. compounds of formula (I) wherein R₇=agroup X (wherein n=1), may be obtained, according to Scheme 2, startingfrom compounds of formula (II), wherein Pg is a suitable N-protectinggroup, typically Boc or benzyl, through deprotection of N-Pg group.

For example, for Boc removal, TFA in DCM at temperature between 0° C.and room temperature may be used.

For example, for N-benzyl removal, either H₂ and Pd/C oralfa-chloroethyl chloroformate at reflux in DCE and then in MeOH may beused.

Compounds of formula (IIb), i.e. compounds of formula (II) whereinR₁₆═C₁₋₄alkyl or C₁₋₃alkylC₃₋₆cycloalkyl and wherein Pg is a suitableN-protecting group, typically Boc or benzyl, may be obtained startingfrom compounds of formula (IIa), wherein R₁₆═H, according to Scheme 3,following standard alkylation procedures, e.g. using a R₁₆Y alkylatingagent (R₁₆═C₁₋₄ alkyl or C₁₋₃alkylC₃₋₆cycloalkyl, Y=halogen), such asCH₃₁, in the presence of a strong base, such as NaH, in aprotic solvent,e.g. DMF, at temperature between 0° C. and room temperature.

Compounds of formula (IIa₁), i.e. compounds of formula (IIa) whereinR₃═R₄═H, may be obtained starting from compounds of formula (III),wherein Pg is a suitable N-protecting group, typically Boc or benzyl,according to Scheme 4, through the standard Simmons-Smithcyclopropanation procedure (using ZnEt₂, CH₂I₂ in DCM).

Compounds of formula (Ic), i.e. compounds of formula (I) whereinR₁═R₃═R₄═R₁₆═H, may be obtained starting from compounds of formula (III)wherein Pg is a suitable N-protecting group, typically Boc, according toScheme 5, through Simmons-Smith cyclopropanation procedure (using ZnEt₂,CH₂I₂ in DCM) modified by adding an amine such as2,6-bis(1,1-dimethylethyl)-4-methylpyridine.

Compounds of formula (IIa₁), i.e. compounds of formula (IIa), whereinR₃═R₄═H and wherein Pg is a suitable N-protecting group, typically Boc,may be obtained starting from compounds of formula (Ic), according toScheme 6, following the standard procedures, for example using Bocanhydride and TEA in DCM at temperature between 0° C. and roomtemperature.

Compounds of formula (IIa₂), i.e. compounds of formula (IIa) whereinR₃═R₄═F, may be obtained starting from compounds of formula (III),according to Scheme 7 using dibromodifluoromethane following the methodreported in the Journal of Fluorine Chemistry (2003), 119(1), 75-80.

Compounds of formula (IIa₃), i.e. compounds of formula (IIa) whereinR₃═R₄═CH₃ may be obtained starting from compounds of formula (III),according to Scheme 8 in analogy with the method reported in Synlett(2002), (1), 176-178, a modified Simmons-Smith cyclopropanationprocedure in which 2,2-diiodopropane is used.

Compounds of formula (III), may be obtained starting from compounds offormula (IV), wherein Pg is a suitable N-protecting group, typicallyBoc, according to Scheme 9, using appropriate reducing agents, such asfor example LiAlH₄, in aprotic solvent e.g. diethyl ether of THF, attemperature between 40 and −10° C.

Compounds of formula (IV), may be obtained starting from compounds offormula (V), according to Scheme 10, following the standard Suzukycoupling procedure using the suitable aryl boronic acids or boronateesters, Pd(PPh₃)₄ and a base, e.g. Na₂CO₃ in a mixture of solvent e.g.toluene, ethanol and water at 80° C.

Compounds of formula (V), wherein —OTf represents a triflate group, maybe obtained according to Scheme 11, starting from compounds of formula(VI), wherein Pg is a suitable N-protecting group, typically Boc, byreaction with a base (eg sodium hydride), and then with a triflatingagent, such as N-phenyltrifluoromethanesulfonimide, in an aproticsolvent (eg DMF), at temperature between 0° C. and room temperature.

Compound of formula (VIa), wherein R₅=═H, and Pg is a suitableprotecting group, such as Boc, may be obtained, according to Scheme 12,by reacting the commercially available compound of formula (VII),wherein R₅═R₆═H, with Boc anhydride and TEA in DCM, at temperaturebetween 0° C. and room temperature.

Compounds of formula (VIb), wherein R₅═R₆═CH₃ and Pg is a suitableprotecting group, may be obtained, according to Scheme 13, throughacylation of compound (VIII), wherein R₅═R₆═CH₃ and Pg is a suitableprotecting group, in analogy with the method reported in J. Org. Chem.,1995, 60, 5825.

Compounds of formula (VIII), wherein R₆═R₅═CH₃ and Pg is a suitableprotecting group, such as Boc, may be prepared starting from compound(IX), wherein R₆═R₅═CH₃, according to Scheme 14, as reported inWO2002085886.

Compounds of formula (Id), i.e. compounds of formula (I) whereinR₁═C₁₋₄alkyl, may be obtained starting from compounds of formula (Ie),according to Scheme 15, with analogous procedures to those describedabove for Scheme 1.

Compounds of formula (Ie₁), i.e. compounds of formula (I) whereinR₆═R₅═H or CH₃, and R₃═R₄═CH₃ may be obtained, according to Scheme 16,starting from compounds of formula (X), in analogy with the methodreported in Synlett (2002), (1), 176-178, a modified Simmons-Smithcyclopropanation procedure in which 2,2-diiodopropane is used, followedby usual N-Pg deprotection.

Compounds of formula (Ie₂), wherein R₆═R₅═H or —CH₃, and R₃═R₄═F, may beobtained starting from compounds of formula (X), according to Scheme 17,using dibromodifluoromethane, as described in the Journal of FluorineChemistry (2003), 119(1), 75-80, followed by usual N-Boc deprotection.

Compounds of formula (Ie₃), i.e. compounds of formula (I), whereinR₆═R₅═H or —CH₃, and R₃═R₄═H, may be obtained starting from compounds offormula (X), according to Scheme 18, through the standard Simmons-Smithcyclopropanation procedure, followed by usual N-Pg deprotection.

Compounds of formula (Ie₄), i.e. compounds of formula (I), whereinR₆═R₅═H or —CH₃ and R₁₆═H, C₁₋₄alkyl or C₁₋₃alkylC₃₋₆cycloalkyl, may beobtained starting from compounds of formula (X₁), wherein R₆═R₅═H or—CH₃ and R₁₀═H, C₁₋₄alkyl or C₁₋₃alkylC₃₋₃cycloalkyl and Pg is asuitable protecting group, according to Scheme 19, after usual N-Pgdeprotection.

Compounds of formula (XIa), i.e. compounds of formula (X₁), wherein R₁,═C₁₋₄alkyl or C₁₋₄alkylC₃₋₆cycloalkyl, may be obtained starting fromcompounds of formula (XIb), as below defined, according to Scheme 20,through standard alkylation procedures, e.g. using a R₁₆Y alkylatingagent (R₁₆═C₁₋₄alkyl, Y=halogen), such as CH₃₁, in the presence of astrong base, such as NaH, in aprotic solvent, e.g. DMF, at temperaturebetween 0° C. and room temperature.

Compounds of formula (XIb), i.e. compounds of formula (X₁), whereinR₁₆═H, may be obtained starting from compounds of formula (XII), whereinR₆═R₅═H or CH₃ and Pg is a suitable protecting group, according toScheme 21, in analogy with the method reported in Synlett (2002), (1),176-178, using ethyl diazoacetate and rhodium acetate, in aproticsolvent (e.g. DCE, DCM or MeCN), at temperature between room temperatureand 80° C., followed by reduction of the ester with an appropriatereducing agent, such as LiAlH₄ or BH₃ THF, at temperature between −20°C. and 70° C.

Compounds of formula (XII), wherein R₆═R₅═H or CH₃ and Pg is a suitableprotecting group, may be obtained starting from compounds of formula(XIII), according to Scheme 22 following the above cited Suzuky couplingprocedure, using the suitable aryl boronic acids or esters.

Compounds of formula (XIII), wherein R₈═R₅═H or CH₃, —OTf represents atriflate group and Pg is a suitable protecting group, may be obtainedstarting from compounds of formula (VIII), wherein R═R₅═H or CH₃ and Pgis a suitable protecting group, according to Scheme 23, by reaction witha base (eg sodium hydride), then with a triflating agent, such asN-phenyltrifluoromethanesulfonimide, in an aprotic solvent (eg DMF), attemperature between 0° C. and room temperature.

Compounds of formula (If), i.e. compounds of formula (I) wherein R₁═C₁₋₄alkyl or C₁₋₃alkylC₃₋₆cycloalkyl, R₅═H, R₆=a group X (wherein n=1,R₁₆═C₁₋₄ alkyl) and R₇═H, may be obtained starting from compounds offormula (Ig), i.e. compounds of formula (I) wherein R₁═H, R₅═H, R₆=agroup X (wherein n=1, R₁₆═C₁₋₄ alkyl or C₁₋₃alkylC₃₋₆cycloalkyl,) andR₇═H, according to Scheme 24, through standard alkylation procedures,e.g. using a R₁Y alkylating agent (R₁═C₁₋₄alkyl, Y=halogen), such asCH₃₁, a trialkylamine, such as TEA, in DCM, at temperature between 0° C.and room temperature. Alternatively, compounds of formula (If) may beobtained by reductive amination using a suitable aldehydeRCHO(R═C₁₋₃alkyl), a reducing agent such as NaCNBH₃, in aprotic orprotic solvent e.g. Toluene, THF or MeOH, at temperature between 80° C.and room temperature.

Compounds of formula (Ig), wherein R₁₆═C₁₋₄alkyl orC₁₋₃alkylC₃₋₆cycloalkyl, may be obtained starting from compounds offormula (XV), through usual N-Pg deprotection procedures according toScheme 25.

Compounds of formula (XV), wherein R₃═R₄═H, F or —CH₃, R₁₆═C₁₋₄ alkyl orC₁₋₃alkylC₃₋₆cycloalkyl, may be obtained, according to Scheme 26,starting from compounds of formula (XVI), wherein R₁₆═C₁₋₄alkyl orC₁₋₃alkylC₃₋₆cycloalkyl, through the method described respectively inthe Schemes 5, 6 and 7.

Compounds of formula (XVI), wherein R₁₆═C₁₋₄alkyl orC₁₋₂alkylC₃₋₆cycloalkyl, may be obtained, according to Scheme 27,starting from compounds of formula (XVII) through alkylation procedureusing a suitable alkylating agent (e.g. MeI) in the presence of a strongbase (e.g. NaH) in an aprotic solvent such as THF or DMF at temperaturebetween 0° C. and room temperature.

Compounds of formula (XVII), wherein Pg is a suitable protecting groupsuch as —CH₂-Ph, may be obtained through the Prins reaction as reportedin European J. of Org. Chemistry, (15), 3336, 2004.

Compounds of formula (Ih), i.e. compounds of formula (I) whereinR₆═R₆═R₅═R₄═R₃═R₁═H, may be isolated through chromatographic separationfrom the corresponding regioisomers of formula (XVIII), as depicted inScheme 28.

Compounds of formula (Ih), i.e. compounds of formula (I) whereinR₆═R₅═R₄═R₃═R₁═H, and compounds of formula (XVIII) may be obtained bythe respective precursors, i.e. compounds of formula (XIX) and (XXX), byreduction for example with borane in THF at refluxing temperature,according to Scheme 29.

Compounds of formula (XIX) and (XXX) may be obtained starting fromcompounds of formula (XXXI) via Beckmann rearrangement for example usingtosyl chloride in acetone from room temperature to reflux, according toScheme 30.

Compounds of formula (XXXI) may be prepared starting from compounds offormula (XXXII), according to Scheme 31, for example using hydroxylaminemonohydrate in ethanol at room temperature.

Compounds of formula (XXXII), may be prepared starting from compounds offormula (XXXIII), according to Scheme 32, by rearrangement of theappropriate propargylic aldehyde after reaction with the allylicderivative (XXXIV) where M can be SiMe₂Cl or MgBr, as described in J.Am. Chem. Soc. 2004, 126, 8654.

Compounds of formula (XXXIII) may be prepared by oxidation for examplewith Dess-Martin periodinane in DCM at room temperature from theappropriate alcohol (XXXV) according to Scheme 33.

Compounds of formula (XXXV) may be prepared from propargyl alcohol andappropriate Iodo arene (XXXVI), in analogy with the method described inJOC, 2005, 70, 4043 and according to Scheme 34.

Compounds of formula (IIa₁), i.e. compounds of formula (IIa) whereinR₃═R₄═H, Pg is a suitable N-protecting group (typically Boc), may beobtained starting from compounds of formula (XXXVII) as below defined,through reduction with borane in THF at refluxing temperature, accordingto Scheme 35.

Compounds of formula (XXXVII), wherein R₃═R₄═R₅═R₆═H, may be obtainedstarting from compounds (XXXVIII), wherein R₃═R₄═R₅═R₆═H, throughreaction with sodium hydride in DMF, at temperature from 0° C. to roomtemperature, for 1-3 h, according to Scheme 36.

Compounds of formula (XXXVIII), wherein R₃═R₄═R₅═R₆═H, may be obtainedstarting from compounds (XXXIX) wherein R₂ is an aromatic orheteroaromatic group, R₃═R₄═R₅═R₆═H, through reaction with mesylchloride and TEA in DCM, at temperature from 0° C. to room temperature,according to Scheme 37.

Compounds of formula (XXXIX), wherein R₃═R₄═R₅═R₆═H, may be obtainedstarting from compounds (XL) wherein R₃═R₄═R₅═R₆═H and Pg a silylprotective group (e.g: 1,1-dimethylethyl)diphenylsilane), for example bystandard Pg removal with TBAF in THF followed by reaction with ammoniumhydroxide in a mixture of solvents, such as THF and methanol, at roomtemperature for several hours, according to Scheme 38

Compounds of formula (XL), wherein R₃═R₄═R₅═R₆═H and Pg a silylprotective group (e.g: 1,1-dimethylethyl)diphenylsilane), may beobtained by reacting compounds (XLI) with diazomalonate (prepared asdescribed in Synthetic Communication, 1987, 17, 1709-1716) and rhodium(II) acetate, at 100° C., in analogy with the method reported inWO/2005/058884, according to Scheme 39.

Compounds of formula (XLI), wherein Pg is a silyl protective group (e.g:1,1-dimethylethyl)diphenylsilane), may be obtained starting fromcompounds (XLII), wherein Pg is defined as before, by the Suzukycoupling procedure using the appropriate aryl or heteroaryl boronicacids or boronate esters, Pd(PPh₃)₄ and a base (e.g. Na₂CO₃), in amixture of solvent (e.g. toluene, ethanol and water) at 80° C.,according to Scheme 40.

When Pg corresponds to the meaning defined above in Scheme 39 and 40,the corresponding compound of formula (XLII),[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane, can beprepared by reacting the corresponding compound of formula (XLIII),3-bromo-3-buten-1-ol, with chloro(1,1-dimethylethyl)diphenylsilane andimidazole in DCM, at room temperature, according to Scheme 41.

Alternatively, compounds of formula (Im), i.e. compounds of formula (I)as above defined wherein R₁, R₃, R₄, R₅, R₆ are hydrogen and R₇ is agroup X (wherein n=1), may be obtained from compounds of formula (XLIV)wherein Pg is a N-protecting group, typically Boc, through deprotectionof N-Pg group according to Scheme 42. For example, when Pg is Boc, usingTFA in DCM at temperature between 0° C. and room temperature.

Compounds of formula (XLIV) as above defined may be obtained startingfrom compounds of formula (XLV), wherein R₁₆═H, following standardalkylation procedures according to Scheme 43, e.g. using a R₁₆Yalkylating agent such as MeI in the presence of a strong base, such asNaH, in aprotic solvent, e.g. DMF, or THF, at temperature between 0° C.and room temperature.

Compounds of formula (XLV) as above defined may be obtained fromcompounds of formula (XLVI) where R_(j) is an alkyl group, according toScheme 44, by simultaneous reduction of amide and ester groups with BH₃or LiAlH₄ in aprotic solvent, mainly THF, at reflux and subsequent “insitu” nitrogen protection with a Pg group, typically Boc, for example byusing Boc anhydride under basic conditions at room temperature.

Compounds of formula (XLVI) may be obtained according to Scheme 45 fromcompounds of formula (XLVII) wherein R_(j) is as above defined and L isa suitable leaving group, by nucleophilic displacement of the leavinggroup (L) e.g. mesylate, with NH₃ in MeOH under pressure in ahydrogenation apparatus (for example Parr), followed under the sameconditions by intramolecular cyclisation of the intermediate amine toamide.

Compounds of formula (XLVII) as above defined, may be obtained accordingto Scheme 46 from compounds of formula (XLVIII), wherein L is as abovedefined, by carbene mediated cyclopropanation with dimethyldiazopropandioate and rhodium catalyst, for example Rh₂(OAc)₂, inchlorinated solvent, e.g, chlorobenzene or DCE, at temperature between40° C. and 80° C. If asymmetric rhodium catalyst is used, the reactioncan be stereospecific.

Compounds of formula (XLVIII), as above defined, may be obtainedaccording to Scheme 47 from compounds of formula (XLIX) by suitableoxygen functionalisation aimed to obtain a leaving group as mesylate ortosylate e.g. using methansulfonyl chloride or tosyl chloride in DCMunder basic condition at 0° C. or room temperature.

Compounds of formula (XLIX) may be obtained according to Scheme 48 fromcompounds of formula (L) following the standard Suzuky couplingprocedure using suitable boronic acids, Pd(PPh₃)₄ and a base e.g. Na₂CO₃in a mixture of solvents e.g. toluene, ethanol and water at 80° C.

Alternatively, compounds of formula (Im), i.e. compounds of formula (I)as above defined wherein R₁, R₃, R₄, R₅, R₆ are hydrogen and R₇ is agroup X (wherein n=1), may be obtained from compounds of formula (LXIV),wherein groups R₂ and R₁₆ are defined as for formula (I), throughdeprotection of t-butoxycarbonyl protecting group and contemporarydouble bond reduction according to Scheme 49. For example, reactionconditions may comprise treatment with trifluoroacetic acid andtriethylsilane in toluene at room temperature. Alternative reducingagents may be used, for example Sodium triacetoxyboronhydride or Sodiumboronhydride. Alternative solvents may also be used, for exampledichloromethane, trifluorotoluene or chlorobenzene.

Compounds of formula (LXIV), as above defined, may be obtained fromcompounds of formula (LI), wherein group R₂ is defined as for formula(I), through alkylation of hydroxyl group with an alkylating agent R₁₆Y[wherein Y is a leaving group, an halogen or a group —OSO₂R(R=aryl oralkyl group)] according to Scheme 50. For example, reaction conditionsmay comprise treatment with potassium hydroxide in DMSO at roomtemperature of compound of formula (LI) and consequent addition of R₁₆Y.Alternative bases may be used, for example sodium hydroxide, potassiumt-butoxide, cesium hydroxide or lithium hydroxide. Alternative solventsmay also be used, for example dichloromethane or tetrahydrofurane.

Compounds of formula (LI), as above defined, may be obtained fromcompounds of formula (LII), wherein group R₂ and X₂ are defined as forformula (I), through reduction of the esther moiety in group X₂according to Scheme 51. For example, reaction conditions may comprisetreatment with lithium boronhydride and EtOH in THF at room temperature.Alternative other reducing agents may be used, for example lithiumaluminiumhydride, sodiumboronhydride or diisobuylaluminium hydride.

Compounds of formula (LII), as above defined, may be obtained fromcompounds of formula (LIII), wherein group R₂ and X₂ are defined as forformula (I), through reaction with an appropriate base in the presenceof the appropriate alkylating agent according to Scheme 52. For example,reaction conditions may comprise treatment with Lithium t-butoxide andCH₂ICl in N-methylpyrrolidone at low temperature (for example −20 to+10° C.). Alternative alkylating agents may be used, for example CH₂I₂.Alternative solvents may be used, for example DMF or THF. Alternativebases may be used, for example LDA or NaH.

Compounds of formula (LIV), as above defined, may be obtained fromcompounds of formula (LV), wherein group X₂ is defined as for formula(I), through coupling reaction with an appropriate boronic acidR₂B(OH)₂, wherein R₂ is as defined for compounds of formula (I),according to Scheme 53. For example, reaction conditions may comprisetreatment with R₂B(OH)₂ as above defined, in the presence of Pd(OAc)₂,PPh₃ and diisopropylethylamine toluene and water at a temperatureranging from room temperature to 80° C. Alternative catalysts may beused, for example Pd(PPh₃)₄, PdCl₂(dppf).

Compounds of formula (LIV), as above defined, may be obtained fromcompounds of formula (LV), wherein group X₂ is defined as for formula(I), through formation of the triflate derivative according to Scheme54. For example, reaction conditions may comprise treatment with triflicanhydride, in the presence of diisopropylethylamine and in toluene at atemperature ranging from 0° C. to room temperature.

Compounds of formula (In), i.e. compounds of formula (I) wherein R₁, R₅,R₆, R₃, R₄ are hydrogen and R₇ is a group X wherein n is 1, may beprepared according to Scheme 55, through the procedures below described,starting from compound of formula (LXII):

Example of Reaction conditions: a=EtOH, 8 hrs, RT; b=BOC₂₀; K₂CO₃, from0° C. to RT for 48 hrs; c=EtONa, Toluene, from 0° C. to RT, overnight;d=1) NaH and1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfony]methanesulfonamide,DMF, 1 h; 2) toluene/EtOH; R₂B(OH)₂, K₂CO₃, Pd(Ph₃P)₄, 80° C., 1 h.;e=LiAlH₄, THF from −20° C. to RT, 2 h.; f=Et₂Zn, CH₂I₂ DCM, RT,overnight.; g=NaH, R₁₈I, DMF, 0° C. to RT.

Compounds of formula (Io), i.e. compounds of formula (I) wherein R₁, R₅,R₆, R₃, R₄ are hydrogen and R₁ is an alkyl group, may be preparedaccording to Scheme 56, starting from compounds of formula (XXX) throughthe procedures below described:

Example of Reaction conditions: a=R₁Y, NaH, DMF; b=R₁₇MgBr, THF,NaCNBH₃.

When a specific enantiomer or diastereoisomer of a compound of formula(I)′ or salts thereof, is required, this may be obtained for example byresolution of a corresponding enantiomeric or diastereoisomeric mixtureusing conventional methods.

Thus, for example, specific enantiomers or diastereoisomers of thecompounds may be obtained from the corresponding enantiomeric ordiastereoisomeric mixture using chiral chromatographic methods such asfor example chiral HPLC (for reference procedure see for exampleseparation of E2a and E3a, of E5a and E6a, of E9a and E10a, of E19a andE20a, of E26a and E27a).

Alternatively, specific enantiomers or diastereoisomers of the compoundsmay be obtained from the corresponding enantiomeric or diastereoisomericmixture using chiral crystallization methods such as precipitation withchiral acids (for reference procedure see for example E34 and E35).

Furthermore a specific enantiomer or diastereoisomer of a compound ofthe invention may be synthesised from the appropriate optically activeintermediate using any of the general processes described herein.

Alternatively, a specific enantiomer or diastereoisomer of a compoundthe invention may be synthesised from the appropriate stereochemicallyenriched intermediate using any of the general processes describedherein and by combining it with any of the conventional resolutionmethods above described.

Optically active intermediates or stereochemically enrichedintermediates, may be generated by resolution of a correspondingenantiomeric or diastereosiomeric mixtures using conventional methods(for reference procedure see for example P60), or by performance ofstereoselective reactions (for reference procedure see for example P67)or by combining different resolution techniques.

Also specific enantiomers or diastereoisomers of the compounds may beobtained by combining conventional methods above described.

The compounds of the present invention are useful in the treatment ofdisorders or diseases responsive to the monoamine neurotransmitterre-uptake inhibiting activity of the compounds. This activity of thecompounds of the invention may make them useful in the treatment ofParkinsonism, depression, eating disorders, sleep disorders, substancerelated disorders, attention-deficit hyperactivity disorders, anxietydisorders, cognition impairment, sexual dysfunctions, obsessivecompulsive spectrum disorders, Gilles de la Tourettes disease and seniledementia, as well as other disorders sensitive to the monoamineneurotransmitter re-uptake-inhibiting activity of the compounds.

Within the context of the present invention, the terms describing someindications used herein are classified in the Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, published by the AmericanPsychiatric Association (DSM-IV) and/or the International Classificationof Diseases, 10th Edition (ICD-10). The various subtypes of thedisorders mentioned herein are contemplated as part of the presentinvention. Numbers in brackets after the listed diseases below refer tothe classification code in DSM-IV.

The term “depression” includes:

Depression and mood disorders including Major Depressive Episode, ManicEpisode, Mixed Episode and Hypomanic Episode; Depressive Disordersincluding Major Depressive Disorder, Dysthymic Disorder (300.4),Depressive Disorder Not Otherwise Specified (311); Other Mood Disordersincluding Mood Disorder Due to a General Medical Condition (293.83)which includes the subtypes With Depressive Features, With MajorDepressive-like Episode, With Manic Features and With Mixed Features),Substance-Induced Mood Disorder (including the subtypes With DepressiveFeatures, With Manic Features and With Mixed Features) and Mood DisorderNot Otherwise Specified (296.80): Bipolar Disorders including Bipolar IDisorder, Bipolar II Disorder (Recurrent Major Depressive Episodes withHypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and BipolarDisorder Not Otherwise Specified (296.80);

The term “anxiety disorders” includes:

Anxiety disorders including Panic Attack; Panic Disorder including PanicDisorder without Agoraphobia (300.01) and Panic Disorder withAgoraphobia (300.21); Agoraphobia; Agoraphobia Without History of PanicDisorder (300.22), Specific Phobia (300.29, formerly Simple Phobia)including the subtypes Animal Type, Natural Environment Type,Blood-Injection-Injury Type, Situational Type and Other Type), SocialPhobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder(300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder(308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due toa General Medical Condition (293.84), Substance-Induced AnxietyDisorder, Separation Anxiety Disorder (309.21), Adjustment Disorderswith Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified(300.00):

The term “substance related disorder” includes:

Substance-related disorders including Substance Use Disorders such asSubstance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-induced Delirium, Substance-induced PersistingDementia, Substance-induced Persisting Amnestic Disorder,Substance-induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-induced Anxiety Disorder, Substance-Induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-inducedPsychotic Disorder, Alcohol-induced Mood Disorder, Alcohol-InducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-induced Psychotic Disorder, Hallucinogen-induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencydidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide;

The term “Sleep disorder” includes:

Sleep disorders including primary sleep disorders such as Dyssomniassuch as Primary Insomnia (307.42), Primary Hypersomnia (307.44),Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), CircadianRhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified(307.47); primary sleep disorders such as Parasomnias such as NightmareDisorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder(307.46) and Parasomnia Not Otherwise Specified (307.47); SleepDisorders Related to Another Mental Disorder such as Insomnia Related toAnother Mental Disorder (307.42) and Hypersomnia Related to AnotherMental Disorder (307.44); Sleep Disorder Due to a General MedicalCondition; and Substance-induced Sleep Disorder including the subtypesInsomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type;

The term “eating disorder” include:

Eating disorders such as Anorexia Nervosa (307.1) including the subtypesRestricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51)including the subtypes Purging Type and Nonpurging Type; Obesity;Compulsive Eating Disorder; Binge Eating Disorder; and Eating DisorderNot Otherwise Specified (307.50):

The term “Attention-Deficit/Hyperactivity Disorder” includes:

Attention-Deficit/Hyperactivity Disorder including the subtypesAttention-Deficit/Hyperactivity Disorder Combined Type (314.01),Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type(314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-impulseType (314.01) and Attention-Deficit/Hyperactivity Disorder Not OtherwiseSpecified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorderssuch as Conduct Disorder including the subtypes childhood-onset type(321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89),Oppositional Defiant Disorder (313.81) and Disruptive Behaviour DisorderNot Otherwise Specified; and Tic Disorders such as Tourette's Disorder(307.23);

The term “Cognition impairment” includes:

Cognition impairment including cognition impairment in other diseasessuch as schizophrenia, bipolar disorder, depression, other psychiatricdisorders and psychotic conditions associated with cognitive impairment,e.g. Alzheimer's disease;

The term “Sexual dysfunctions” includes:

Sexual dysfunctions including Sexual Desire Disorders such as HypoactiveSexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79);sexual arousal disorders such as Female Sexual Arousal Disorder (302.72)and Male Erectile Disorder (302.72); orgasmic disorders such as FemaleOrgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) andPremature Ejaculation (302.75); sexual pain disorder such as Dyspareunia(302.76) and Vaginismus (306.51); Sexual Dysfunction Not OtherwiseSpecified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism(302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism(302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3),Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9);gender identity disorders such as Gender Identity Disorder in Children(302.6) and Gender Identity Disorder in Adolescents or Adults (302.85);and Sexual Disorder Not Otherwise Specified (302.9);

The term “Obsessive compulsive spectrum disorder” includes:

Obsessive compulsive spectrum disorder including Obsessive compulsivedisorders (300.3), somatoform disorders including body dysmorphicdisorder (300.7) and hyperchondriasis (300.7), bulimia nervosa (307.51),anorexia nervosa (307.1), eating disorders not elsewhere classified(307.50) such as binge eating, impulse control disorders not elsewhereclassified (including intermitted explosive disorder (312.34),compulsive buying or shopping, repetitive self-mutilation, onychophagia,psychogenic excoriation, kleptomania (312.32), pathological gambling(312.31), trichotillomania (312.39) and internet addiction), paraphilia(302.70) and nonparaphilic sexual addictions, Sydeham's chorea,torticollis, autistic disorders (299.0), compulsive hoarding, andmovement disorders, including Tourette's syndrome (307.23).

All of the various forms and sub-forms of the disorders mentioned hereinare contemplated as part of the present invention.

In an embodiment, compounds of the invention may be useful asanalgesics. For example they may be useful in the treatment of chronicinflammatory pain (e.g. pain associated with rheumatoid arthritis,osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenilearthritis); musculoskeletal pain; lower back and neck pain; sprains andstrains; neuropathic pain; sympathetically maintained pain; myositis;pain associated with cancer and fibromyalgia; pain associated withmigraine; pain associated with influenza or other viral infections, suchas the common cold; rheumatic fever; pain associated with functionalbowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain andirritable bowel syndrome; pain associated with myocardial ischemia; postoperative pain; headache; toothache; and dysmenorrhea.

Compounds of the invention may be useful in the treatment of neuropathicpain. Neuropathic pain syndromes can develop following neuronal injuryand the resulting pain may persist for months or years, even after theoriginal injury has healed. Neuronal injury may occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain syndromes are traditionally classified according to thedisease or event that precipitated them. Neuropathic pain syndromesinclude: diabetic neuropathy; sciatica; non-specific lower back pain;multiple sclerosis pain; fibromyalgia; HIV-related neuropathy;post-herpetic neuralgia; trigeminal neuralgia; and pain resulting fromphysical trauma, amputation, cancer, toxins or chronic inflammatoryconditions. These conditions are difficult to treat and although severaldrugs are known to have limited efficacy, complete pain control israrely achieved. The symptoms of neuropathic pain are incrediblyheterogeneous and are often described as spontaneous shooting andlancinating pain, or ongoing, burning pain. In addition, there is painassociated with normally non-painful sensations such as “pins andneedles” (paraesthesias and dysesthesias), increased sensitivity totouch (hyperesthesia), painful sensation following innocuous stimulation(dynamic, static or thermal allodynia), increased sensitivity to noxiousstimuli (thermal, cold, mechanical hyperalgesia), continuing painsensation after removal of the stimulation (hyperpathia) or an absenceof or deficit in selective sensory pathways (hypoalgesia).

Compounds of the invention may also be useful in the amelioration ofinflammatory disorders, for example in the treatment of skin conditions(e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmicdiseases such as glaucoma, retinitis, retinopathies, uveitis and ofacute injury to the eye tissue (e.g. conjunctivitis); lung disorders(e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratorydistress syndrome, pigeon fancier's disease, farmer's lung, chronicobstructive pulmonary disease, (COPD); gastrointestinal tract disorders(e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritisvarialoforme, ulcerative colitis, coeliac disease, regional ileitis,irritable bowel syndrome, inflammatory bowel disease, gastroesophagealreflux disease); other conditions with an inflammatory component such asmigraine, multiple sclerosis, myocardial ischemia.

In one embodiment, compounds of the invention are useful in thetreatment of depression and anxiety disorders.

In another embodiment, compounds of the invention are useful in thetreatment of depression.

“Treatment” includes prophylaxis, where this is appropriate for therelevant condition(s).

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofdisorders or diseases responsive to the monoamine neurotransmitterre-uptake inhibiting activity of the compounds, comprisingadministration of an effective amount of a compound of the invention.

In one embodiment, the invention provides a method of treating acondition for which inhibition of serotonin (5-HT), dopamine (DA) andnorepinephrine (NE), is beneficial, which comprises administering to amammal (e.g. human) in need thereof an effective amount of a compound ofthe invention.

In another embodiment, the invention provides a method of treating acondition for which inhibition of serotonin (5-HT), dopamine (DA) andnorepinephrine (NE), is beneficial, which comprises administering to amammal (e.g. human) in need thereof an effective amount of(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof.

In a further embodiment, the invention provides a method of treatingdepression which comprises administering to a mammal (e.g. human) inneed thereof an effective amount of(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a method of treating acondition for which inhibition of serotonin (5-HT), dopamine (DA) andnorepinephrine (NE), is beneficial, which comprises administering to amammal (e.g. human) in need thereof an effective amount of (1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound of the inventionfor use in therapy.

In a further embodiment, the invention provides a compound of theinvention for use in the treatment of a condition in a mammal for whichinhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) isbeneficial.

In one aspect, the invention provides the use of compounds of theinvention, for the manufacture of a medicament for the treatment ofdisorders or diseases responsive to monoamine neurotransmitter re-uptakeinhibiting activity.

In one embodiment, the invention provides the use of a compound of acompound of the invention in the manufacture of a medicament for thetreatment of a condition in a mammal for which inhibition of serotonin(5-HT), dopamine (DA) and norepinephrine (NE) is beneficial.

In a further embodiment, the invention provides the use of(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of a condition in a mammal for whichinhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) isbeneficial.

In another embodiment, the invention provides the use of (1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of a condition in a mammal for whichinhibition of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) isbeneficial.

The compounds of the invention may also be used in combination withother therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention togetherwith a further therapeutic agent.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent psychotic disorders: i)antipsychotics; ii) drugs for extrapyramidal side effects, for exampleanticholinergics (such as benztropine, biperiden, procyclidine andtrihexyphenidyl), antihistamines (such as diphenhydramine) anddopaminergics (such as amantadine); iii) antidepressants; iv)anxiolytics; and v) cognitive enhancers for example cholinesteraseinhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention may be used in combination withantidepressants to treat or prevent depression and mood disorders.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent bipolar disease: i) moodstabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent anxiety disorders: i) anxiolytics;and ii) antidepressants.

The compounds of the invention may be used in combination with thefollowing agents to improve nicotine withdrawal and reduce nicotinecraving: i) nicotine replacement therapy for example a sublingualformulation of nicotine beta-cyclodextrin and nicotine patches; and ii)bupropion.

The compounds of the invention may be used in combination with thefollowing agents to improve alcohol withdrawal and reduce alcoholcraving: i) NMDA receptor antagonists for example acamprosate; ii) GABAreceptor agonists for example tetrabamate; and iii) Opioid receptorantagonists for example naltrexone.

The compounds of the invention may be used in combination with thefollowing agents to improve opiate withdrawal and reduce opiate craving:i) opioid mu receptor agonist/opioid kappa receptor antagonist forexample buprenorphine; ii) opioid receptor antagonists for examplenaltrexone; and iii) vasodilatory antihypertensives for examplelofexidine.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent sleeping disorders: i)benzodiazepines for example temazepam, lormetazepam, estazolam andtriazolam; ii) non-benzodiazepine hypnotics for example zolpidem,zopiclone, zaleplon and indiplon; iii) barbiturates for exampleaprobarbital, butabarbital, pentobarbital, secobarbita andphenobarbital; iv) antidepressants; v) other sedative-hypnotics forexample chloral hydrate and chlormethiazole.

The compounds of the invention may be used in combination with thefollowing agents to treat anorexia: i) appetite stimulants for examplecyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; andv) premenstral agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent bulimia: i) antidepressants; ii)opioid receptor antagonists; iii) antiemetics for example ondansetron;iv) testosterone receptor antagonists for example flutamide; v) moodstabilisers; vi) zinc; and vii) premenstral agents.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent autism: i) antipsychotics; ii)antidepressants; iii) anxiolytics; and iv) stimulants for examplemethylphenidate, amphetamine formulations and pemoline.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent ADHD: i) stimulants for examplemethylphenidate, amphetamine formulations and pemoline; and ii)non-stimulants for example norepinephrine reuptake inhibitors (such asatomoxetine), alpha 2 adrenoceptor agonists (such as clonidine),antidepressants, modafinil, and cholinesterase inhibitors (such asgalantamine and donezepil).

The compounds of the invention may be used in combination with thefollowing agents to treat personality disorders: i) antipsychotics; ii)antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent male sexual dysfunction: i)phosphodiesterase V inhibitors, for example vardenafil and sildenafil;ii) dopamine agonists/dopamine transport inhibitors for exampleapomorphine and buproprion; iii) alpha adrenoceptor antagonists forexample phentolamine; iv) prostaglandin agonists for examplealprostadil; v) testosterone agonists such as testosterone; vi)serotonin transport inhibitors for example serotonin reuptakeinhibitors; v) noradrenaline transport inhibitors for example reboxetineand vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the sameagents specified for male sexual dysfunction to treat or prevent femalesexual dysfunction, and in addition an estrogen agonist such asestradiol.

Antipsychotic drugs include Typical Antipsychotics (for examplechlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindoneand loxapine); and Atypical Antipsychotics (for example clozapine,olanzapine, risperidone, quetiapine, aripirazole, ziprasidone andamisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such ascitalopram, escitalopram, fluoxetine, paroxetine and sertraline); dualserotonin/noradrenaline reuptake inhibitors (such as venlafaxine,duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such asreboxetine); tricyclic antidepressants (such as amitriptyline,clomipramine, imipramine, maprotiline, nortriptyline and trimipramine);monoamine oxidase inhibitors (such as isocarboxazide, moclobemide,phenelzine and tranylcypromine); and others (such as bupropion,mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproicacid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate andtiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of the invention and apharmaceutically (i.e physiologically) acceptable carrier. Thepharmaceutical composition can be for use in the treatment of any of theconditions described herein.

In one embodiment, a pharmaceutical composition comprising(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptaneor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier is provided.

The compounds of the invention may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of the invention which are active when given orally can beformulated as liquids or solids, for example syrups, suspensions oremulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or salt in a suitable liquid carrier(s) for example anaqueous solvent such as water, ethanol or glycerine, or a non-aqueoussolvent, such as polyethylene glycol or an oil. The formulation may alsocontain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous carrier or parenterallyacceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluoro-chlorohydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

In one embodiment, the composition is in unit dose form such as atablet, capsule or ampoule.

Each dosage unit for oral administration contains for example from 0.5to 250 mg (and for parenteral administration contains for example from0.05 to 25 mg) of a compound of the invention calculated as the freebase.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, for example between 1mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, forexample between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a salt thereof calculated as the freebase, the compound being administered 1 to 4 times per day, for example1 to 2 time a day. In one embodiment, the compound of the invention maybe administered once a day. Suitably the compounds will be administeredfor a period of continuous therapy, for example for a week or more.

For oral administration a typical dose may be in the range of 1 to 200mg per day, for example 60 to 200 mg per day.

When a compound of the invention or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art. It will beappreciated that the amount of a compound of the invention required foruse in treatment will vary with the nature of the condition beingtreated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations by any convenient route.

The invention is also directed to a novel kit-of-parts that is suitablefor use in the treatment of disorders as above defined comprising afirst dosage form comprising a compound of the invention and a seconddosage form comprising another therapeutic agent, for simultaneous,separate or sequential administration.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

Biological Assays Cell Biology

a) Generation of Stable LLCPK Cell Lines Expressing hSERT, hNET, andhDAT

Stable cell line expressing human serotonin transporter (hSERT) may becreated by transfecting Lewis Lung Carcinoma Porcine tubule Kidney(LLC-PK1 or LLCPK) cells with hSERT cloned into the mammalian expressionvector pcDNA3.1 Hygro(+).

Stable cell line expressing human norepinephrine transporter (hNET) maybe created by transfecting LLCPK cells with hNET cloned into themammalian expression vector pRC/CMV.

Stable cell line expressing human dopamine transporter (hDAT) may becreated by transfecting LLCPK cells with hDAT cloned into the mammalianexpression vector pDESTCDNA3.1.

One example of reference procedure for transfecting LLCPK cells withhDAT, hSERT and hNET may be found in H. Gu, S. C. Wall and G. Rudnick,J. Biol. Chem. (1994) 269 7124-7130.

Each cell line is cultured independently in Dulbecco's modified Eagle'smedium (DMEM) containing 10% of Foetal Bovine Serum (FBS) supplementedwith 400 μg/ml hygromycin (hSERT) or geneticin at 500 μg/ml (hNET) or at1000 μg/ml (hDAT). Cells are maintained at 37° C. in a humidifiedenvironment containing 5% CO₂ in air.

b) Generation of BacMam Viruses for the Expression of hSERT, hNET, andhDAT in Mammalian Cells

Membranes for the SPA-binding assays are produced by HEK-293F cellinfection with BacMam viruses generated for each single human SERT, NET,and DAT transporter. hSERT and hDAT are cloned into pFBMRfA vectorwhereas hNET is cloned into pFASTBacMam1 vector. The generation and useof BacMam viruses is described in Condreay J P et al, Proc. Natl. Acad.Sci. USA, 1999, 96:127-132 and Hassan N J et al, Protein Expression andPurification, 47(2): 591-598, 2006.

Affinity to the Human Transporters SERT, NET and DAT

The affinities of the compounds of the invention for the human serotonintransporter (SERT), human norepinephrine transporter (NET) and for thehuman dopamine transporter (DAT) may be determined by one of the assaysdescribed below. Such affinity is typically calculated from the IC₅₀obtained in competition experiments as the concentration of a compoundnecessary to displace 50% of the radiolabeled ligand from thetransporter, and is reported as a “K_(i)” value calculated by thefollowing equation:

$K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

where L=radioligand and K_(D)=affinity of radioligand for transporter(Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973). In the contextof the present invention pKi values (corresponding to the antilogarithmof Ki) are used instead of Ki; pKi results are only estimated to beaccurate to about 0.3-0.5.a) Filtration Binding Assay on Membranes Form hSERT, hNET, and hDATLLCPK Cell Lines

Membrane Preparation

hSERT-LLCPK or hDAT-LLCPK or hNET-LLCPK cell lines are used for themembrane preparations for radioligand binding assays. Each cell line iscultured independently in Dulbecco's modified Eagle's medium (DMEM)containing 10% of Foetal Bovine Serum (FBS) supplemented with 400 μg/mlhygromycin (hSERT) or geneticin at 500 μg/ml (hNET) or at 1000 μg/ml(hDAT). When cells are at 70-80% of confluence, the culture medium isremoved and the cells harvested with phosphate buffered saline (PBS)containing 5 mM EDTA. Cell suspension is centrifuged at 900 g for 5minutes at 4° C. The resultant pellets are re-suspended in 30-50 volumesof Assay Buffer (50 mM Tris pH 7.7 containing 120 mM NaCl, 5 mM KCl, 10μM pargyline and 0.1% ascorbic acid) and homogenized using aglass-teflon Potter homogeniser and centrifuged at 48000 g for 20minutes at 4° C. The resultant membrane pellets are re-suspended in thesame volume of Assay Buffer, incubated for 20 minutes at 37° C. andcentrifuged as before at 48000 g. The final protein concentration foreach preparation is adjusted to give approximately 480 μg protein/ml forhSERT-LLCPK, hDAT-LLCPK and hNET-LLCPK, as determined by the Bio-RadProtein Assay kit. Membranes are stored at −80° C. as 1 ml aliquotsuntil required.

Filtration Assay Protocol for hSERT, hNET, and hDAT

General references for monoamine transporters filtration binding assaymay be: Michael J. Owens, et al, Neurotransmitter receptor andtransporter binding profile of antidepressants and their metabolites,JPET, 283:1305-1322, 1997; Per Allard, Jan O. Marcusson, Svate B. Ross,[3H]WIN-35,428 binding in the human brain, Brain Res., 706: 347-350,1996.

The affinity of the compounds of the invention to bind the re-uptakesite of SERT may be assessed using [³H]citalopram filtration bindingassay performed on hSERT-LLCPK cell membranes. In details, competitionbinding assay is conducted in deep-well 96 well plate (1 ml, NUNC,cod.260252) in a total volume of 400 μl, with each concentration induplicate, 4 μl of test compound (100× solution in neat DMSO as 7 pointcurve ranging from 10⁻⁶ to 10⁻¹²M, final concentration) or DMSO (todefine total binding) or a final concentration of 10 μM fluoxetine inDMSO (to define non-specific binding, NSB) are added to wells; afterthis, 200 μl of [N-Methyl-3H]citalopram (Amersham Biosciences, 80Ci/mmol) at the final concentration of 0.25 nM in Assay Buffer, is addedto all wells and finally the reaction is started by adding 200 μl/wellof membranes diluted 1:80 in Assay Buffer at concentration of about 2.5μg/well of protein. The reaction is carried out at room temperature for2 hours and then stopped by rapid filtration through GF/B Unifilter96-filterplate (Perkin-Elmer) pre-soaked in 0.5% polyethylenimine (PEI)using a Perkin-Elmer FilterMat-196 harvester. Filterplate is washed 3times with 1 ml/well ice-cold 0.9% NaCl solution. The plate is dried inan oven for 60 min at 50° C. then opaque bottom-seal is placed on theunderside of the plate and 50 μl of Microscint 20 (Perkin-Elmer) addedto each well. Plate is sealed with a TopSeal and the radioactivity inthe samples is counted for 4 min using TopCount liquid scintillationcounter (Packard-Perkin-Elmer) and recorded as counts per minute (CPM).

Competition binding assay for hNET may be conducted essentially aspreviously reported for hSERT in 96 well format and in a final assayvolume of 400 μl, except for the use of hNET-LLCPK cell membranes (1:40dilution i.e. 4.8 μg of protein/well) and [³H]nisoxetine as radioligand(1.5 nM [N-methyl-3H]nisoxetine, Amersham Biosciences, 84 Ci/mmol). 10μM desipramine is used for NSB.

Competition binding assay for hDAT may be conducted essentially aspreviously reported for hSERT and hNET in 96 well format and in a finalassay volume of 400 μl, except for the use of hDAT-LLCPK cell membranes(1:20 i.e. 9.6 μg of protein/well) and [³H]WIN-35,428 as radioligand (10nM [N-Methyl-3H]WIN-35,428, Perkin Elmer, 85.6 Ci/mmol).

Furthermore, 10 μM GBR-12909 is used for NSB and the incubation time ofthe binding reaction is 1 hour at room temperature.

b) Scintillation Proximity Assay (SPA) for Human DAT, NET and SERTBinding

Transduction of HEK-293F Cells with hSERT/hDAT/hNET BacMam Viruses

The HEK-293F suspension cell line (Invitrogen) is routinely grown in293_Freestyle Expression media (Invitrogen) in shake flask suspensionculture. The culture is transduced with the appropriate transporterBacMam at a MOI (multiplicity of infection) of 100 virus particles percell and incubated for 48 hrs at 37° C., 5% CO₂ in air, shaken at 90 rpmin a humidified shaker incubator. The culture is then harvested bycentrifugation at 1000 g, 4° C., for 10 minutes and the cell pelletstored at −80° C. until required.

Preparation of BacMam hSERT/hDAT/hNET-HEL293F Cell Membranes

Transduced cell pellets are re-suspended to 10× volume with buffer-A (50mM HEPES, 1 mM EDTA, 1 mM leupeptin, 25 ug/mL bacitracin, 1 mMphenylmethylsulfonylfluoride, PMSF, 2 μM pepstatin A, pH 7.7) andhomogenised with 2×15 second bursts in a glass Waring blender. Thehomogenate is then centrifuged for 20 minutes at 500 g. Following this,the supernatant is pooled and centrifuged at 13,000 g for 30 minutes.Pellets are then re-suspended to 4× original pellet volume with buffer-B(50 mM TRIS pH 7.4, 130 mM NaCl) and forced through a 0.8 mm needle togive a homogeneous suspension. Membrane aliquots are stored at −80° C.until required. The protein concentration is quantified by Bradfordassay.

SPA-Binding Assay Protocol for hSERT, hNET, and hDAT

The affinity of the compounds of the invention to the hSERT, hNET orhDAT can be also assessed by using the [³H]citalopram, [³H]nisoxetine or[³H]WIN-35,428 binding assays with the SPA technology onBacMam-recombinant human SERT, NET and DAT membranes produced asdescribed before. With the SPA technology (GE Healthcare, Amersham) onlytransporter-bound radioactivity can elicit bead excitation thus noseparation of the bound/unbound radioligand is required.

The protocol for hSERT binding SPA is based on Trilux beta-counter(Wallac, Perkin-Elmer). Briefly, 0.5 μL of test compound in neat DMSO(or 1 μM fluoxetine as positive control) is added by 50 μL of the SPAmixture, containing 2 mg/mL SPA beads (Amersham RPNQ0001), 4 μg/mL hSERTBacmam membranes, 0.01% pluronic F-127, 2.5 nM [³H]citalopram in theassay buffer (20 mM HEPES, 145 mM NaCl, 5 mM KCl, pH 7.3). Incubationare performed at room temperature for at least 2 hours. Counts arestable and could be read up to 3 days.

Alternatively, hDAT hNET and hSERT SPA-binding assays are performed byusing a Viewlux beta-counter (Wallac, Perkin-Elmer) with imaging PS-WGAbeads (Amersham RPNQ0260) in a final assay volume of 30 μL and in a384-well plate format (Greiner 781075). Briefly, 0.3 μL of test compoundin neat DMSO and 0% and 100% effect controls (DMSO for total binding and10 or 1 μM indatraline as positive control) are added to the wells byusing a Hummingbird (Genomic Solutions), followed by the addition of 30μL of the SPA mixture, containing 1 mg/mL SPA beads (hSERT) or 2 mg/mlSPA beads (hDAT and hNET), 40 μg/ml or 20 μg/ml or 6 μg/ml of hDAT orhNET or hSERT BacMam membranes, 0.02% pluronic F-127, 10 nM[³H]WIN-35,428 or 10 nM [³H]nisoxetine or 3 nM [³H]citalopram for hDATor hNET or hSERT binding SPA in the assay buffer (20 mM HEPES, 145 mMNaCl, 5 mM KCl, pH 7.3-7.4). Incubation is performed at room temperaturefor at least 2 hours, best overnight in the dark. Bound radioactivity isrecorded by using a 600 s 6× binning and 613 nm emission filter with theViewlux instrument.

Compound Affinity Range for Human Transporters SERT, NET, and DAT

The compounds of formula (I)′ typically show pKi greater than 4.5towards each of the three transporters SERT, NET and DAT. In oneembodiment, the compounds of formula (I) typically show pKi greater than5.5 for each of the three transporters. In another embodiment, thecompounds of formula (I)′ typically show pKi greater than 6.5 for eachof the three transporters. In a further embodiment, the compounds offormula (I)′ typically show pKi greater than 7.5 for each of the threetransporters.

In one embodiment, the present invention provides compounds of formula(I)′ having a hSERT pKi comprised between 7 and 8.5. In anotherembodiment, the present invention provides compounds of formula (I)′having a hSERT pKi comprised between 8.5 and 10.

In one embodiment, the present invention provides compounds of formula(I) having a hDAT pKi comprised between 6.5 and 7.5. In anotherembodiment, the present invention provides compounds of formula (I)′having a hDAT pKi comprised between 7.5 and 8.5.

In one embodiment, the present invention provides compounds of formula(I)′ having a hNET pKi comprised between 6.5 and 7.5. In anotherembodiment, the present invention provides compounds of formula (I)′having a hNET pKi comprised between 7.5 and 8.5.

In one embodiment, the present invention provides compounds of formula(I)′ having a a hSERT pKi comprised between 8.5 and 10, a hNET pKicomprised between 7.5 and 8.5 and a hDAT pKi comprised between 7.5 and8.5.

In one embodiment, the present invention provides compounds of formula(I)′ having a hSERT pKi comprised between 9 and 10, a hNET pKi comprisedbetween 8.0 and 8.5 and a hDAT pKi comprised between 7.5 and 8.0.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples.

In the procedures that follow, after each starting material, referenceto a Preparation or Example by number is typically provided. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

Where reference is made to the use of a “similar” or “analogous”procedure, as will be appreciated by those skilled in the art, such aprocedure may involve minor variation, for example reaction temperature,reagent/solvent amount, reaction time, work-up conditions orchromatographic purification conditions.

Compounds are named using ACD/Name PRO 6.02 chemical naming software(Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

All temperatures refer to ° C.

Proton Magnetic Resonance (NMR) spectra are typically recorded either onVarian instruments at 300, 400 or 500 MHz, or on a Bruker instrument at300 and 400 MHz. Chemical shifts are reported in ppm (d) using theresidual solvent line as internal standard. Splitting patterns aredesigned as s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; b, broad. The NMR spectra were recorded at a temperatureranging from 25 to 90° C. When more than one conformer was detected thechemical shifts for the most abundant one is reported.

Mass spectra (MS) are typically taken on a 4 II triple quadrupole MassSpectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer,operating in ES (+) and ES (−) ionization mode or on an Agilent LC/MSD1100 Mass Spectrometer, operating in ES (+) and ES (−) ionization modecoupled with HPLC instrument Agilent 1100 Series. In the mass spectraonly one peak in the molecular ion cluster is reported.

When HPLC walk-up retention time is reported, the analysis is done on aHPLC Agilent 1100 Series Instrument with the following method: Column:Luna C18 100 A 50×2 mm, 3 micron; Mobile Phase: (MeCN+0.05%TFA)/(H2O+0.05% TFA) gradient 0/100 to 95/5 in 8 minutes; Flux 1 ml/min.

Flash silica gel chromatography was carried out on silica gel 230-400mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be—Sipre-packed cartridges or over pre-packed Biotage silica cartridges.

In a number of preparations, purification was performed using eitherBiotage manual flash chromatography (Flash+) or automatic flashchromatography (Horizon or SP1) systems. All these instruments work withBiotage Silica cartridges.

X-Ray Powder Diffraction (XRPD): It will be recognised that spectra anddiffraction data will vary slightly according to various factors such asthe temperature, concentration and instrumentation used. The skilledperson will recognise that XRPD peak positions are affected bydifferences in sample height. The peak positions quoted herein are thussubject to a variation. The skilled person will also recognise that therelative intensities of peaks may change due to preferred orientationeffects.

Differential Scanning Calorimetry (DSC): It should be recognized thatthe endotherm peak as measured is dependent under a number of factorsincluding the machine employed, the rate of heating, the calibrationstandard, humidity and the purity of the sample used. Melting pointsreported in the experimentals are estimated on the basis of the onset ofendotherm peaks registered during DSC analysis.

The following abbreviations are used in the text:TBAF=tetrabutylammonium fluoride, DCE=dichloroethane, Tic refers to thinlayer chromatography on silica plates, and dried refers to a solutiondried over anhydrous sodium sulphate, r.t. (RT) refers to roomtemperature, Rt=retention time, DMSO=dimethyl sulfoxide;DCM=dichloromethane; DMF=N,N′-dimethylformamide; MeOH=methanol; TEA orEt₃N=triethylamine; THF=tetrahydrofurane; EA, AcOEt or EtOAc=ethylacetate; cy=cyclohexane; EtOH=ethyl alcohol; ZnEt₂=diethylzinc;MTBE=methyl t-butyl ether; TFA=trifluoroacetic acid; Et₂O=diethyl ether;IPA=isopropyl alcohol;DMPU=1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; SPECartridge=Solid Phase Extraction Cartridge; SCX Cartridge=Strong

Cation Exchange Cartridge; MCX: mixed mode-cation exchange cartridge; NHcolumn: secondary amine functionalised silica cartridge.

Preparation 1: 1-(1,1-dimethylethyl) 3-methyl4-hydroxy-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P1)

To a stirred solution of methyl 4-oxo-3-piperidinecarboxylatehydrochloride (14.94 g) in dry DCM (250 mL), at 0° C. and under anitrogen atmosphere, TEA (43 mL) was added dropwise over 5 minutes. Themixture was stirred at 0° C. for 5 minutes, then allowed to reach roomtemperature, bis(1,1-dimethylethyl) dicarbonate (18.6 g) was then addedin one portion and the solution was left stirring overnight at roomtemperature under Nitrogen. Saturated aqueous NH₄Cl solution (350 ml)was poured into the solution and the mixture was transferred in aseparator funnel. The reaction flask was washed with DCM (100 ml) andthis volume was poured into the separator funnel. The phases wereseparated and the watery one was washed with DCM (3×70 mL). The combinedorganic phases were dried on anhydrous Na₂SO₄, the solvent removed underreduced pressure, the crude product purified by flash-chromatography(eluting with ethyl acetate/cyclohexane 1:3) to give the title compound(19.8 g.).

NMR (¹H, CDCl₃): δ 11.95-12.02 (m, 1H) 4.07 (br. s., 2H) 3.77-3.82 (m,3H) 3.58 (t, 2H) 2.34-2.43 (m, 2H) 1.46-1.50 (m, 9H)

Preparation 2: 1-(1,1-dimethylethyl) 3-methyl4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P2)

Method A: to a stirred solution of 1-(1,1-dimethylethyl) 3-methyl4-oxo-1,3-piperidine-dicarboxylate (500 mg, P1) in dry DMF (5 mL) at 0°C. and under a nitrogen atmosphere, NaH (60% on mineral oil, 117 mg) wasadded portionwise and the reaction mixture was stirred at 0° C. for 10minutes, then a solution of N-phenyl-bis(trifluoromethanesulfonimide)(0.847 g) in dry DMF (2 mL) was added dropwise and stirring wascontinued for 0.5 h. Saturated NH₄Cl (30 mL) and diethyl ether (30 mL)were poured into the reaction mixture, the phases were separated and thewatery one was washed with diethyl ether (3×15 mL). The combined organicphases were dried on anhydrous Na₂SO₄ and the solvent was removed underreduced pressure to give 1.5 g. of the crude title compound.

Method B: to a stirred solution of 1-(1,1-dimethylethyl) 3-methyl4-oxo-1,3-piperidinedicarboxylate (500 mg, P1) in dry THF (12 mL) at 0°C. and under a nitrogen atmosphere, NaH (60% on mineral oil, 156 mg) wasadded portionwise and the reaction mixture was stirred at 0° C. for 30minutes, then N-phenyl-bis(trifluoromethanesulfonimide) (1.028 g) wasadded in one portion and stirring was continued at 0° C. for 1 hour andat rt overnight. 10 g of ice were poured into the stirred mixture andTHF was evaporated at rt under reduced pressure. The residue was takenup with ethyl acetate (30 mL) and the mixture was washed with aqueousNa₂CO₃ (10%, 3×20 mL). The organic layer was dried on anhydrous Na₂SO₄and the solvent was removed under reduced pressure, obtaining 1.7 g. ofthe crude title compound.

The crude products from Method A and B were combined and purified byflash-chromatography (eluting with ethyl acetate/cycloexane 1:9) to give1.340 g. of the title compound.

NMR (¹H, CDCl₃): δ 4.29 (br. s., 2H) 3.82-3.87 (m, 3H) 3.64 (t, 2H)2.50-2.57 (m, 2H) 1.46-1.52 (m, 9H). MS (m/z): 390 [MH]+, 412 [MNa]+.

Preparation 3: 1-(1,1-dimethylethyl) 3-methyl4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P3)

To a mixture of 1-(1,1-dimethylethyl) 3-methyl4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(200 mg, P2), 3,4-dichlorophenylboronic acid (108 mg) and Pd(PPh₃)₄ (21mg) under nitrogen, toluene (2.5 mL), ethanol (2 mL) and Na₂CO₃ (aqueous2M solution, 2 mL) were added in sequence. The mixture was stirred at80° C. for 1 hour then the reaction mixture was allowed to reach roomtemperature. Saturated aqueous NH₄Cl solution (15 mL) was poured intothe solution and the mixture was transferred in a separator funnel. Themixture was extracted with ethyl acetate (3×20 mL), the combined organicphases were dried on anhydrous Na₂SO₄ and the solvent evaporatedobtaining a crude product that was purified by flash-chromatography(eluting with ethyl acetate/cycloexane 1:3) to give the title compound(198 mg).

NMR (¹H, CDCl₃): δ 7.42 (d, 1H) 7.25 (d, 1H) 6.98 (dd, 1H) 4.26 (br. s.,2H) 3.61 (t, 2H) 3.55-3.58 (m, 3H) 2.47 (br. s., 2H) 1.50-1.54 (m, 9H)

Preparation 4:1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P4)

To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (538mg, P3,) in dry diethyl ether (10 mL) under N₂ atmosphere, at −20° C.,LiAlH₄ (1M in diethyl ether, 1 mL) was added dropwise over 1 minute, thereaction mixture was left stirring at −20° for 15 minutes then aqueoussaturated NH₄Cl solution (50 mL) and diethyl ether (50 mL) were pouredinto the solution and the mixture was vigorously stirred for 20 minutesat room temperature. The phases were separated, and the watery one wasextracted with diethyl ether (3×20 mL). The combined organic phases weredried on anhydrous Na₂SO₄ and the solvent was removed under reducedpressure, obtaining a crude product that was purified byflash-chromatography (eluting with ethyl acetate/cycloexane 1:3) to givethe title compound (474 mg).

NMR (¹H, DMSO-d6): δ 7.62 (d, 1H) 7.56 (d, 1H) 7.26 (dd, 1H) 4.90 (t,1H) 4.02 (br. s., 2H) 3.79 (d, 2H) 3.49 (t, 2H) 2.35 (br. s., 2H)1.42-1.46 (m, 9H)

Preparation 5:(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P5)

Method A:

To a stirred solution of CH₂I₂ (13.39 g) in dry DCM (83 mL) under Argonatmosphere, at 0° C., ZnEt₂ (1M in hexane, 25 mL) was added dropwise,the mixture was stirred at 0° C. for 20 minutes and then cooled at −20°C. At this point a solution of1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridine-carboxylate(734 mg, P4) in dry DCM (3.5 mL) was added dropwise, the reactionmixture was stirred for additional 30 mins, then 40 mins at 0° C. andovernight at room temperature. Saturated aqueous NH₄Cl solution (100 mL)was poured into the reaction flask and the mixture was vigorouslystirred for 10 minutes, the phases were separated and the organic layerwas evaporated under reduced pressure. The residue was taken up withdiethyl ether (50 mL) and this volume was added to the previous NH₄Clsolution: the total mixture was poured into a separator funnel. Theorganic phase was treated with saturated NH₄Cl (3×20 mL), then with HCl(5%) (20 mL), the organic and aqueous acidic phases were separated andsubmitted to two different processing.

The organic phase was evaporated obtaining a crude product (280 mg) thatwas purified by flash-chromatography (eluting with ethylacetate/cycloexane 1:3) to give the still impure title compound (70 mg).

The watery phase was washed with diethyl ether (50 mL) and stronglybasified with NaOH 2N, then the basic solution was extracted withdiethyl ether (3×50 mL), the combined organic phases were dried onanhydrous Na₂SO₄ and the solvent was removed under reduced pressure,obtaining a crude material (210 mg) containing as major component[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol)].

MS (m/z): 272 [MH]⁺.

A portion of this crude material (159 mg) was dissolved in dry DCM (5mL) under Argon atmosphere and stirred at rt, bis(1,1-dimethylethyl)dicarbonate (156 mg) was added at room temperature and the mixture wasleft stirring overnight. The solvent was evaporated under reducedpressure and the residue was taken up with diethyl ether (15 mL). Thissolution was washed with saturated NH₄Cl (15 mL), the watery phase wasextracted with diethyl ether (3×10 mL), the combined organic phases weredried on anhydrous Na₂SO₄ and the solvent was removed under reducedpressure obtaining a crude product that was combined with the previouslyobtained 70 mg of the impure title compound. This material was againpurified by flash-chromatography (eluting with diethyl ether/n-hexane1:2 to 1:1) to give a still impure title compound as a mixture with1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(170 mg).

MS (m/z): 372 [MH]⁺.

Method B: bis(1,1-dimethylethyl) dicarbonate (838 mg) was added at roomtemperature to a solution of[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(840 mg, E4, impure compound obtained as described in E4, Method A) indry DCM (25 mL), and the mixture was stirred overnight. The mixture washeated at 40° C. for 2 hours and then cooled at room temperature.Saturated NH₄Cl (50 mL) and DCM (20 mL) were added to the reactionmixture and, after stirring for 10 mins, the phases were separated. Theorganic phase was evaporated and the residue was dissolved in diethylether (50 mL). The organic phase was washed with saturated NH₄Cl (3×30mL), was dried on anhydrous Na₂SO₄ and the solvent was removed underreduced pressure. The crude oil (920 mg) obtained was purified byflash-chromatography (eluting with ethyl acetate/cyclohexane 1:3) togive an impure title compound as a mixture with1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridine-carboxylate(260 mg) and impure 1,1-dimethylethyl(1R,6S)-6-(3,4-dichlorophenyl)-1-[({[(1,1-dimethylethyl)oxy]carbonyl}oxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(185 mg) [MS (m/z): 472 [MH]⁺].

1,1-dimethylethyl(1R,6S)-6-(3,4-dichlorophenyl)-1-[{[(1,1-dimethylethyl)oxy]carbonyl}oxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylatewas dissolved in MeOH (7 mL) under argon and the stirred solution wascooled at 0°. NaOH (0.5 M, 3 mL) was added dropwise and the mixture wasstirred for 20 mins at 0° C., 30 mins at 50° C. and 1.5 hours at 70° C.MeOH was evaporated under reduced pressure, the watery residue wasdiluted with water (20 mL) and extracted with diethyl ether (3×20 mL).The combined organic phases were dried on anhydrous Na₂SO₄ and thesolvent was removed under reduced pressure to give another batch of thestill impure title compound as a mixture with1,1-dimethylethyl-4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(130 mg).

MS (m/z): 372 [MH]⁺.

Method C: to a stirred solution of methyl6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P16, 0.19 g) in THF (3 mL), at 0° C. and under a nitrogen atmosphere,BH₃THF complex (1M/THF, 2.38 mL) was added dropwise, then the reactionmixture was allowed to reach RT and stirred at reflux for 4 h. Thereaction mixture was cooled to 0° C. and the pH was adjusted to 2-3 withaqueous 20% HCl solution, then the ice-bath was removed and the mixturewas stirred at RT for 15 min. DCM was added and the pH was brought to8-9 with aqueous 2N NaOH solution. The organic phase was washed withbrine, dried over Na₂SO₄ and the solvent evaporated under reducedpressure. The crude product was dissolved in DCM, Boc₂O (0.136 g) wasadded and the reaction mixture stirred for 1 h at RT. The reaction wasextracted with ether, the organic phase washed with aqueous saturatedNaHCO3 solution, brine, dried over Na2SO4 and the solvent removed underreduced pressure to give 0.195 g of the crude Title compound as acolourless oil that was used without any further purification.

Preparation 6:(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P6)

To a stirred solution of (1S,6R/1R,6S)-1,1-dimethylethyl6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(110 mg, P5, impure compound obtained as described in P5, Method A) indry THF (2 mL) under Argon atmosphere, at 0° C., NaH (60% on mineraloil, 11.7 mg) was added in one portion and the stirring continued for 30minutes. After this period CH₃I (18.2 μL) was added dropwise and thereaction was allowed to reach room temperature and stirred for 1.5 h,then an additional amounts of NaH (5.3 mg) and CH₃I (8.3 μL) were added.The reaction mixture was left stirring for 2 hour at room temperature,then was cooled to 0° C., aqueous saturated NH₄Cl solution (15 mL) anddiethyl ether (20 mL) were added and the mixture was vigorously stirredfor 10 minutes at room temperature. The phases were separated and thewatery one was extracted with diethyl ether (3×10 mL). The combinedorganic phases were washed with brine (3×20 mL), dried on anhydrousNa₂SO₄, the solvent evaporated obtaining a crude product (106 mg) thatwas purified by flash-chromatography (eluting with diethylether/n-hexane 40:60) to give the still impure titled compound as amixture with 1,1-dimethylethyl4-(3,4-dichlorophenyl)-5-[(methyloxy)methyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(80 mg).

MS (m/z): 386 [MH]⁺

Preparation 7: 3-(3,4-dichlorophenyl)-2-propyn-1-ol (P7)

Method A: The title compound (2.94 g) was prepared in analogy with themethod described in JOC 2005, 70, 4043-4053 starting from3,4-dichloroiodobenzene (4 g, two preparation were carried out).

Method B: a mixture of 3,4-dichloroiodobenzene (300 mg), propargylalcohol (128 μL), CuI (10 mg), K₂CO₃ (302 mg), Pd(PPh₃)₄ (12 mg) in DMF(2 mL) was irradiated with MicroWave at 100° C. for 20 min. Aqueoussaturated solution NH₄Cl was then added followed by DCM. Afterseparation of the two phases the organic layer was dried and evaporatedin vacuo. The crude product was purified by flash chromatography(eluting with cyclohexane/ethyl acetate 7/3) to give the title compound(40 mg).

NMR (¹H, CDCl₃): δ 7.58 (s, 1H), 7.41 (d, 1H), 7.27 (d, 1H), 4.52 (d,2H), 1.75 (t, 1H)

Preparation 8: 3-(3,4-dichlorophenyl)-2-propynal (P8)

To a solution of 3-(3,4-dichlorophenyl)-2-propyn-1-ol (2.980 g, P7, fromMethod A and B described for P7) in dry DCM (74 mL) and Dess-Martinperiodinane (9.43 g) was added. The mixture was stirred at roomtemperature over night. NaS₂O₃ (19 g) and NaHCO₃ saturated solution werethen added to the mixture and it was stirred at room temperature for 1hour. Then the organic phase was separated and washed with brine. Theorganic layer was dried and concentrated under reduced pressure to givethe crude title product (2.9 g) that was used without furtherpurification.

NMR (¹H, CDCl₃): δ 9.48 (s, 1H), 7.73 (s, 1H), 7.55 (d, 1H), 7.42 (m,1H).

Preparation 9:(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (P9)

The title compound was prepared in analogy with the method described inJ. Am. Chem. Soc. 2004, 126, 8654 from 3-(3,4-dichlorophenyl)-2-propynal(2.9 g, P8) in 880 mg yield as an orange foam.

NMR (¹H, CDCl₃): δ 7.45 (d, 1H), 7.28 (s, 1H), 7.11 (d, 1H), 2.89 (m,2H), 2.70 (d, 1H), 2.42 (d, 1H), 2.05 (m, 1H), 1.38 (m, 1H), 0.72 (m,1H).

Preparation 10:(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one oxime(P10)

To a solution of hydroxylamine mono hydrate (1.26 g) and sodium acetate(2.3 g) in water (7 mL), a solution of(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (0.860 g,P9) in ethanol (18 ml) was added at room temperature and the reactionmixture was stirred over night. After ethanol elimination under reducedpressure, the aqueous solution was extracted with DCM. The organic phasewas dried and concentrated under reduced pressure to give the titlecompound (870 mg).

NMR (¹H, CDCl₃): δ 7.40 (d, 1H), 7.26 (m, 1H), 7.05 (m, 1H), 3.33-2.60(m, 4H), 1.89 (m, 1H), 1.15 (m, 1H), 0.68 (m, 1H). MS (m/z): 256 [MH]+.

Preparation 11:(1R,6R/1S,6S)-1-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one and(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one(P11)

To a solution of(1S,5S/1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one oxime(0.870 g, P10) in acetone (29 ml) sodium carbonate (solution 5% w/w inwater, 25 ml) was added. Then, under vigorous stirring, a solution oftosyl chloride (969 mg) in acetone was added and the mixture stirred atroom temperature for 30 minutes. The reaction mixture was heated atreflux for 4 h and at room temperature over night. After acetoneelimination under reduced pressure, the residue was dissolved in NaHCO₃saturated solution and it was extracted with DCM. The organic phase wasdried and concentrated under reduced pressure. The crude was purified byflash chromatography (DCM/MeOH from 98/2 to 95/5) to give 640 mg of themixture of title compounds.

MS (m/z): 256 [MH]+.

Preparation 12:[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (P12)

The title compound was prepared in 8.7 g yield as a colourless oil,following an analogous procedure to that reported in WO2005058884,starting from 3-bromo-3-buten-1-ol (4 g),chloro(1,1-dimethylethyl)diphenylsilane (8.27 ml), imidazole (2.34 g)and N,N-dimethyl-4-pyridinamine (0.025 g).

Preparation 13:{[3-(3,4-dichlorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsilane(P13)

[(3-Bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (P12, 3.50g) and (3,4-dichlorophenyl)boronic acid (2.06 g) were dissolved intoluene (45 mL), the stirred solution was degassed, thentetrakis(triphenylphosphine)palladium(0) (0.363 g) and ethanol (33 mL)were added and the mixture was degassed again. A 2N aqueous solution ofNa₂CO₃ (24 mL) was added and the mixture was heated to 80° C. andstirred under nitrogen atmosphere for 3 h at this temperature. Aftercooling to RT, the reaction mixture was extracted with ethyl ether, theorganic phase was washed with brine, dried over Na₂SO₄ and the solventremoved under reduced pressure. The crude product was purified by flashchromatography (eluting with cy/EA from 100/0 to 95/5) to give the titlecompound (2.65 g) as a colourless oil.

NMR (¹H, CDCl₃): δ 7.55-7.69 (m, 4H), 7.40-7.47 (m, 3H), 7.34-7.40 (m,4H), 7.32 (d, 1H), 7.11 (dd, 1H), 5.25 (dd, 2H), 3.75 (t, 2H), 2.28-3.12(m, 2H), 0.62-1.26 (m, 9H).

Preparation 14: dimethyl2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate(P14)

{[3-(3,4-Dichlorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsilane(P13, 2.25 g), dimethyl diazopropanedioate (1.2 g) (prepared in ananalogous manner as reported in Synthetic Communications, 17(4),1709-16, 1987) and rodhium (II) acetate dimer (0.060 g) were mixedtogether and heated at 100° C. for 40 min. After cooling, the residuewas treated with DCM and the mixture was filtered. The filtrate wasevaporated under reduced pressure and the crude product was purified byflash chromatography (Cy/EA from 1/0 to 95/5) to give the title compound(2.38 g) as a colourless oil.

NMR (¹H, CDCl₃): δ 7.51-7.61 (m, 4H), 7.25-7.47 (m, 8H), 7.05 (dd, 1H)3.83 (s, 3H), 3.45 (s, 3H), 3.30-3.62 (m, 2H), 2.00-2.29 (m, 2H), 1.83(d, 1H), 1.57 (s, 1H), 0.94-1.13 (m, 9H).

Preparation 15: methyl1-(aminocarbonyl)-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)cyclopropanecarboxylate(P15)

Tetrabutylammonium fluoride (TBAF) (5.6 mL, 1.1 M/TFH) was addeddropwise to a stirred solution of dimethyl2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate(P14, 2.38 g) in THF (27 mL), at 0° C. After 4 h the ice-bath wasremoved and the reaction mixture was stirred for 3 h at RT. The solventwas removed under reduced pressure, the residue was treated with etherand water, the organic phase washed with brine, dried over Na₂SO₄ andthe solvent evaporated under vacuum to give the crude lactoneintermediate (2.08 g). This product was dissolved in a mixture of THF(15 mL) and methanol (10 mL), at RT, aqueous NH₄OH (28%, 16 mL) wasadded dropwise and the reaction mixture was stirred for 4 h. The mixturewas concentrated under reduced pressure, the residue was taken up withDCM and water, the organic phase was washed with brine, dried overNa₂SO₄ and the solvent evaporated under vacuum. The crude product waspurified by FC (eluting with DCM/methanol from 1/0 to 9/1) to give thetitle compound (0.89 g) as a white foam.

NMR (¹H, CDCl₃): δ 8.14 (br. s., 1H), 7.60 (dd, 1H), 7.41-7.50 (m, 2H),5.79 (br. s., 1H), 3.47-3.59 (m, 2H), 3.13-3.15 (m, 3H), 2.29-2.33 (m,1H), 2.23-2.26 (m, 1H), 2.04-2.22 (m, 2H).

Preparation 16: methyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P16)

a stirred solution of methyl1-(aminocarbonyl)-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)cyclopropanecarboxylate(P15, 0.46 g) in DCM (6 mL), at 0° C., triethylamine (0.25 mL) was addedfollowed by methanesulfonyl chloride (0.16 mL). The ice-bath was removedand the reaction mixture was stirred at RT for 3 h. The mixture wasextracted with further DCM, the organic phase washed with saturatedNH₄Cl, brine, dried over Na₂SO₄ and the solvent evaporated under reducedpressure to give 0.54 g of the intermediate mesylate as a white foam. Toa stirred solution of this product in DMF (6 mL), at RT, NaI (0.22 g)was added followed by NaH (60% in oil, 63 mg) portionwise, and thereaction mixture was stirred for 0.5 h. The reaction mixture wasextracted with ether and NH₄Cl solution, the organic phase washed withwater, brine, dried over Na₂SO₄ and the solvent evaporated under vacuum.The crude product was purified by FC (eluting with cy/EA from 9/1 to1/9) to give the Title product (0.19 g).

NMR (¹H, CDCl₃): δ 7.45 (d, 1H) 7.39 (d, 1H) 7.19 (dd, 1H) 5.79 (br. s.,1H) 3.52 (s, 3H) 3.29-3.38 (m, 1H) 3.20-3.28 (m, 1H) 2.37 (td, 1H) 2.29(d, 1H) 2.12-2.17 (m, 1H) 1.97 (d, 1H). MS (m/z): 314 [MH]⁺.

Preparation 18: ethyl 3-{[3-(ethyloxy)-3-oxopropyl]amino}butanoate (P18)

A solution of ethyl 3-aminobutanoate (4.2 g) and of ethyl 2-propenoate(3.83 mL) in EtOH (20 mL) was stirred at room temperature for 8 h. Thesolvent was evaporated under reduced pressure and the residue purifiedby chromatography on NH column eluting with a gradient from 100%cyclohexane to 90% ethyl acetate/cyclohexane. The title compound wasisolated as a colourless oil, 3.9 g (MS (m/z): 232 [MH]⁺.

Preparation 19: ethyl3-{{[(1,1-dimethylethyl)oxy]carbonyl}[3-(ethyloxy)-3-oxopropyl]amino}butanoate(P19)

A mixture containing ethyl 3-{[3-(ethyloxy)-3-oxopropyl]amino}butanoate(P18, 3.5 g), 1,4-dioxane (8.1 mL), water (16.2 mL) and a 5% solution ofpotassium carbonate (8.4 mL) was cooled with an ice-bath. Di-tert-butyldicarbonate (3.51 mL) was added slowly with stirring. The stirring wasmaintained for 15 min and then continued at room temperature for 3 h.The mixture was left at room temperature for 48 hours. Afterconcentration under reduced pressure, the residue was extracted withdiethyl ether (2×200 mL). The ethereal phase was washed first with 1NHCl, then with water (20 mL) and finally dried. Evaporation of thesolvents afforded a crude material (4.6 g) which was then used withoutfurther purification.

NMR (¹H, CDCl₃): δ 4.08-4.20 (m, 4H), 3.64-3.72 (m, 1H), 3.32-3.53 (m,2H), 2.39-2.74 (m, 4H), 1.43-1.52 (m, 9H), 1.19-1.33 (m, 9H)

Preparation 20:1-(1,1-dimethylethyl) 3-ethyl4-hydroxy-6-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate and1-(1,1-dimethylethyl) 3-ethyl4-hydroxy-2-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P20)

Ethyl3-{{[(1,1-dimethylethyl)oxy]carbonyl}[3-(ethyloxy)-3-oxopropyl]amino}butanoate(P19, 2.5 g) was dissolved in toluene (15 mL) and added at 0° C. to asolution of sodium ethoxide preformed by adding slowly and portionwisesodium hydride 60% dispersed on mineral oil (0.453 g) to a solution ofethanol (0.7 mL) in toluene (5 mL). The mixture was stirred at roomtemperature overnight. Then the solvent was evaporated under reducedpressure and the residue dissolved in ethyl acetate (20 mL), washed with1N HCl (20 mL), dried and concentrated under vacuum. Purification byflash chromatography on silica gel eluting with a gradient 5-50% ethylacetate/cyclohexane afforded the title compounds as pale yellow oil (0.7g) as mixture of regioisomers.

MS (m/z): 230 [M-56]⁺, 186 [MH-100]⁺.

Preparation 21: 1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-6-methyl-5,6-dihydro-1,3(2H-pyridinedicarboxylateand 1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-2-methyl-5,6-dihydro-1,3(2M-pyridinedicarboxylate(P21)

To a stirred solution of a mixture of regioisomers 1-(1,1-dimethylethyl)3-ethyl 6-methyl-4-oxo-1,3-piperidinedicarboxylate and1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-2-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P20, 0.7 g) in dry DMF (6 mL) at 0° C. under nitrogen, sodium hydride60% dispersed on mineral oil (0.118 g) was added portionwise and thereaction mixture was stirred at 0° C. for 10 min. Then a solution of1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide(0.88 g) in dry DMF (1 mL) was added dropwise and stirring was continuedfor 1 h. Saturated NH₄Cl (10 mL) and diethyl ether (30 mL) were pouredinto the reaction mixture. The organic phase was separated, dried andconcentrated under vacuum. The residue was then purified bychromatography on silica gel eluting with a gradient 5-50% ethylacetate/cyclohexane.

The isolated material (MS (m/z): 440 [M+Na]⁺, 362 [MH-56]⁺), (0.65 g)was dissolved in a mixture toluene (15 mL) and ethanol (11 mL);(3,4-dichlorophenyl)boronic acid (0.357 g) and sodium carbonate 2.0Msolution (4.7 mL) were added and the suspension was degassed with asteam of nitrogen for few minutes. Then Pd(Ph₃P)₄ (0.045 g) was addedand the reaction mixture was heated to 80° C. for 1 h. Then it wascooled to room temperature, the solvent was evaporated under reducedpressure and the residue partitioned between ethyl acetate (50 mL) andwater (50 mL). The organic layer was washed with brine (20 mL), driedand concentrated. Purification by chromatography on silica gel elutingwith a gradient 5-25% ethyl acetatecyclohexane afforded the titlecompounds as a mixture of regioisomers as pale yellow oil (0.45 g).

MS (m/z): 437 [M+Na]⁺.

Preparation 22: 1,1-dimethylethyl4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate(P22)

A mixture of regioisomers 1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-6-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylateand 1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-2-methyl-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P21, 0.45 g) was dissolved in toluene (15 mL) and cooled to −20° C.Lithium aluminium hydride 1.0M in THF (0.869 mL) was added dropwise at−20° C. and the mixture was stirred at this temperature for 2 h. Thereaction was then quenched with a saturated solution of NH₄Cl (10 mL)and diluted with ethyl acetate (20 mL); the organic layer was separated,washed with water (20 mL), dried and concentrated in vacuo. Purificationby chromatography on silica gel eluting with a gradient 100%cyclohexane-50% cyclohexane/ethyl acetate afforded 240 mg of titlecompound as colourless oil. The structure of the major regioisomer wasconfirmed by nOe NMR experiments.

NMR (¹H, CDCl₃): δ 7.42 (d, 1H), 7.28 (d, 1H), 7.03 (dd, 1H), 4.52-4.63(m, 1H), 4.44-4.45 (m, 1H), 3.97-4.09 (m, 2H), 3.69-3.79 (m, 1H),2.69-2.81 (m, 1H), 2.00-2.08 (m, 1H), 1.47-1.54 (m, 9H), 1.38-1.43 (m,1H), 1.19 (d, 3H).

Preparation 23:({3-[4-chloro-3-(trifluoromethyl)phenyl]-3-buten-1-yl}oxy)(1,1-dimethylethyl)diphenylsilane(P23)

The title compound (1.85 g) was obtained starting from[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (P12, 1.0g) according to a similar procedure to that previously described forPreparation 13.

NMR (¹H, CDCl₃): δ 7.17-7.22 (m, 1H), 7.08-7.15 (m, 4H), 6.83-6.98 (m,7H), 6.77-6.80 (m, 1H), 4.87-4.91 (m, 1H), 4.69-4.74 (m, 1H), 3.22-3.30(m, 2H), 2.22-2.29 (m, 2H), 0.50-0.56 (m, 9H).

Preparation 24:dimethyl-2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate(P24)

The title compound (1.92 g) was obtained as a colourless oil startingfrom({3-[4-chloro-3-(trifluoromethyl)phenyl]-3-buten-1-yl}oxy)(1,1-dimethylethyl)diphenylsilane(P23, 1.85 g) according to a similar procedure to that previouslydescribed for Preparation 14.

NMR (¹H, CDCl₃): δ 7.50-7.62 (m, 5H), 7.29-7.46 (m, 8H), 3.82-3.85 (m,3H), 3.50-3.59 (m, 1H), 3.36-3.44 (m, 4H), 2.17-2.26 (m, 2H), 1.85-1.89(m, 1H), 1.59-1.72 (m, 1H), 1.01-1.08 (m, 9H)

Preparation 25:methyl-1-(aminocarbonyl)-2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-hydroxyethyl)cyclopropanecarboxylate(P25)

The title compound (0.64 g) was obtained as a white solid aftercrystallization from DCM/5% hexane) by reacting dimethyl2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate(P24, 1.92 g) with TBAF 1.1M in THF (4.7 mL) in THF 20 mL and thentreating the crude intermediate with NH₄OH 28% (14 mL) in a mixture THF(10 mL)/MeOH (7 mL), according to a similar procedure to that previouslydescribed for Preparation 15.

NMR (¹H, CDCl₃): δ 8.18 (br. s., 1H), 7.59-7.61 (m, 1H), 7.46-7.48 (m,1H), 7.44-7.46 (m, 1H), 5.79 (br. s., 1H), 3.48-3.58 (m, 2H), 3.14-3.15(m, 3H), 2.30-2.33 (m, 1H), 2.23-2.26 (m, 1H), 2.05-2.22 (m, 2H)

Preparation 26: methyl(1R,6S/1S,6R)-6-[4-chloro-3,4-trifluoromethyl)phenyl]-2oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P26)

The title compound (0.35 g) was obtained reacting methyl1-(aminocarbonyl)-2-[4-chloro-3-(trifluoromethyl)phenyl]-2-(2-hydroxyethyl)cyclopropanecarboxylate(P25, 0.64 g) with Et₃N (0.37 mL) and trifluoromethane sulfonyl chloride(0.19 mL) in DCM (10 mL) and then treating the intermediate with sodiumhydride 60% dispersed on mineral oil (84 mg) in DMF (5 mL), according toa similar procedure to that previously described for Preparation 16,Method A.

NMR (¹H, CDCl₃): δ 7.64-7.73 (m, 1H), 7.45-7.48 (m, 2H), 6.83 (br. s.,1H), 3.47-3.50 (m, 3H), 3.32-3.41 (m, 1H), 3.19-3.28 (m, 1H), 2.26-2.42(m, 2H), 2.11-2.19 (m, 1H), 2.00-2.04 (m, 1H).

Preparation 27: 1,1-dimethylethyl(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P27)

To a stirred solution of(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P26, 0.35 g) in THF (8 mL), at 0° C. and under a nitrogen atmosphere,BH₃THF complex (1M/THF, 4.03 mL) was added dropwise, then the reactionmixture was allowed to reach RT and stirred at reflux for 4 h. Thereaction mixture was cooled to 0° C. and the pH was adjusted to 2-3 withaqueous 20% HCl, then the ice-bath was removed and the mixture wasstirred at RT for 15 min. DCM was added and the pH was brought to 8-9with 2N NaOH. The organic phase was separated, dried over Na₂SO₄ and thesolvent evaporated under reduced pressure. The crude product thusobtained (310 mg) was treated with di-tert-butyl dicarbonate (220 mg) inDCM (10 mL) at at 0° C. and stirred under these conditions for 1 hour.Then NH₄Cl was added, the organic phase was separated and washed withNaHCO₃, brine, dried and evaporated under reduced pressure to give acrude. This was the purified by flash chromathography eluting withAcOEt/Cy 1:9 to 1:1 to afford the title compound (300 mg).

MS (m/z): 406 [MH]⁺, 350 [MH-56]⁺.

Preparation 28: 1-(1,1-dimethylethyl) 3-methyl4-oxo-1,3-piperidinedicarboxylate (P28)

To an ice cooled suspension of methyl 4-oxo-3-piperidinecarboxylatehydrochloride (15.01 g) in dichloromethane (250 mL) was addedbis(1,1-dimethylethyl) dicarbonate (17.76 g), then triethylamine (27 mL)was added dropwise. The resulting mixture was allowed to reach roomtemperature and stirred for 4 h. Saturated NH₄Cl was poured into thereaction mixture and the phases were separated, the organic layer wasdried over Na₂SO₄, filtered and evaporated under reduced pressure.Diethylether was added to the residue and filtered over a celite pad.The solvent was removed under reduced pressure to obtain the titlecompound (16.96 g).

MS (m/z): 258 [MH]⁺, 202 [MH-56]⁺.

Preparation 29: 1-(1,1-dimethylethyl) 3-methyl4-(4-chlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P29)

To an ice cooled solution of 1-(1,1-dimethylethyl) 3-methyl4-oxo-1,3-piperidinedicarboxylate (P28, 8.5 g) in N,N-dimethylformamide(85 mL), sodium hydride 60% in mineral oil (1.46 g) was added and theresulting mixture was stirred for 10 min at 0° C. To the mixture wasadded a solution of1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide(12.39 g) in N,N-dimethylformamide (62 mL) and the resulting mixture wasallowed to room temperature and stirred for 1 h. Diethylether andsaturated NH₄Cl were added. The aqueous layer was washed withdiethylether, and then the collected organic layers were washed withwater. The organic phase was dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude was purified by flash-chromatography(eluting with cyclohexane/ethylacetate from 1/0 to 9/1) to obtain1-(1,1-dimethylethyl) 3-methyl4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(7.73 g). To a solution of this compound (3 g) and(4-chlorophenyl)boronic acid (1.38 g) in toluene (41 mL), a solution ofPd(PPh₃)₄ (0.32 g) in ethanol (30 mL) was added followed by Na₂CO₃ (2M,22.5 mL) and the resulting mixture was heated at 80° C. for 2 h. Thereaction mixture was allowed to reach room temperature, thendiethylether was added and the phases were separated. The organic layerwas dried over Na₂SO₄, filtered and evaporated under reduced pressure.The resulting crude was purified by flash-chromatography (eluting withcyclohexane/ethylacetate from 1/0 to 8/2) to afford the title compound(2.35 g).

MS (m/z): 352 [MH]⁻, 296 [MH-56]⁺.

Preparation 30: 1,1-dimethylethyl4-(4-chlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P30)

To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl4-(4-chlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P29, 1.85g) in diethylether (37.04 mL) at −20° C., LiAlH₄ 1M solution indiethylether (3.68 mL) was added dropwise and the resulting mixture wasstirred at −20° C. for 20 min. A solution of HCl 2% in water (4.44 mL),diethylether and water were added and the organic phase was separated,dried over Na₂SO₄, filtered and evaporated under reduced pressure toobtain the title compound (1.487 g).

NMR (¹H, CDCl₃): δ ppm 7.33 (d, 2H) 7.12 (d, 2H) 4.13 (s, 2H) 4.03 (s,2H) 3.61 (t, 2H) 2.40 (s, 2H) 1.46-1.52 (m, 9H)

Preparation 31: 1,1-dimethylethyl(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P31).

To an ice cooled suspension of diethylzinc (1M in hexane, 24.07 mL) inanhydrous dichloromethane (19.6 mL), diiodomethane (3.88 mL) was addedand the resulting mixture was stirred for 15 min. To the cooled mixturewas rapidly added a solution of 1,1-dimethylethyl4-(4-chlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P30, 1.04 g) in anhydrous dichloromethane (11.3 mL), allowed to reachroom temperature and then 2,6-bis(1,1-dimethylethyl)-4-methylpyridine(9.88 g) was added and then the mixture stirred for 2 h. Aqueous HCl(1M, 30 mL) was added and left stirring for 30 min. The organic phasewas separated and extracted with HCl, the acid phase was basified withNaOH 3M to reach pH-12 and then extracted with diethylether. The organiclayer was separated, dried over Na₂SO₄, filtered and evaporated underreduced pressure. The resulting crude was purified viaflash-chromatography (eluting with dichloromethane/methanol/ammonia,90(7.5/2.5) to obtain a mixture of[6-(4-chlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol and[4-(4-chlorophenyl)-1,2,5,6-tetrahydro-3-pyridinyl]methanol (190 mg),which was solubilized (188 mg) in anhydrous dichloromethane (8 mL). Tothat solution bis(1,1-dimethylethyl) dicarbonate (181.15 mg) was addedand the resulting mixture was stirred for 2 h. Triethylamine (0.055 mL)was then added dropwise and the mixture stirred for 2 h. Dichloromethane(5 mL) and saturated NH₄Cl (10 mL) were added and the mixture wasvigorously stirred for 10 min. The organic layer was separated, driedover Na₂SO₄, filtered and evaporated under reduced pressure to obtainthe title compound, still impure for the presence of 1,1-dimethylethyl4-(4-chlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(270 mg).

MS (m/z): 338 [MH]⁺, 282 [MH-56]⁺; 324 [MH]⁺, 270 [MH-56]⁺.

Preparation 32: 1,1-dimethylethyl(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P32)

Impure 1,1-dimethylethyl(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P31, 270 mg) and NaH (60% in mineral oil, 28.8 mg) was degassed with asteam of nitrogen, then N,N-dimethylformamide (7.5 mL) was added at 0°C. The resulting mixture was allowed to reach room temperature andstirred for 30 min. Iodomethane (0.099 mL) was added dropwise and leftstirring for 2 h. Three further additions of NaH (60% in mineral oil,9.6 mg, 9.6 mg and 19.2 mg rispectively) at 0° C. and of iodomethane(0.049 mL, 0.049 ml and 0.074 mL rispectively) were made, and overallthe mixture was stirred for 18 h. After this period of time,ethylacetate, water and ice were poured into the mixture and the phaseswere separated. The organic layer was washed with brine, dried overNa₂SO₄ and evaporated under reduced pressure to obtain the titlecompound impure for the presence of 1,1-dimethylethyl4-(4-chlorophenyl)-5-[(methyloxy)methyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(280 mg).

MS (m/z): 352 [MH]⁺, 296 [MH-56]⁺; 338 [MH]⁺.

Preparation 33: 1-(1,1-dimethylethyl) 3-methyl4-{4-[(trifluoromethyl)oxy]phenyl}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P33)

To a mixture of 1-(1,1-dimethylethyl) 3-methyl4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(2.5 g, P2), {4-[(trifluoromethyl)oxy]phenyl}boronic acid (1.52 g) andPd(PPh₃)₄ (265 mg) under nitrogen, toluene (34 mL), ethanol (25 mL) andNa₂CO₃ (2M, 19 mL) were added in sequence. The mixture was stirred at80° C. for 2 hours then the reaction mixture was allowed to reach roomtemperature. The aqueous phase was extracted with Et₂O (2 times), thecombined organic phases were dried on anhydrous Na₂SO₄ and the solventwas evaporated obtaining a crude product that was purified byflash-chromatography (eluting with ethyl acetate/cyclohexane from 1:9 to3:7) to give the title compound (2.5 g)

NMR (¹H, CDCl₃): δ ppm 7.10-7.27 (m, 4H) 4.13-4.35 (m, 2H) 3.57-3.68 (m,2H) 3.53 (s. 3H) 2.30-2.58 (m, 2H) 1.53 (s, 9H); MS (m/z): 402 [MH]⁺.

Preparation 34:1,1-dimethylethyl-5-(hydroxymethyl)-4-{(4-[(trifluoromethyl)oxy]phenyl}-3,6-dihydro-1(2H)-pyridinecarboxylate(P34)

To a stirred solution of 1-(1,1-dimethylethyl) 3-methyl4-{4-[(trifluoromethyl)oxy]phenyl}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P33, 2 g) in dry diethyl ether (40 mL) under N₂ atmosphere, at −20° C.,LiAlH₄ (1M in diethyl ether, 3.6 mL) was added dropwise. The reactionmixture was left stirring at −200 for 20 minutes then saturated NH₄Cland diethyl ether were poured into the solution and the mixture wasvigorously stirred for 30 minutes at room temperature. The two phaseswere separated, and the aqueous layer was extracted with diethyl ether.The combined organic phases were dried on anhydrous Na₂SO₄ and thesolvent was removed under reduced pressure, obtaining the title compound(1.69 g).

NMR (¹H, CDCl₃): δ ppm 7.12-7.26 (m, 4H) 4.15 (s, 2H) 3.95-4.09 (m, 2H)3.63 (t, 2H) 2.31-2.52 (m, 2H) 1.53 (s, 9H); MS (m/z): 374 [MH]⁺.

Preparation 35:(1S,6R/1R,6S)-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]hept-1-yl)methanol(P35)

To a stirred solution of CH₂I₂ (36 g) and2,6-bis(1,1-dimethylethyl)-4-methylpyridine (28 g) in dry DCM (150 mL)under N₂ atmosphere, at 0° C., ZnEt₂ (1M in hexane, 68 mL) was addeddropwise; the mixture was stirred at 0° C. for 30 minutes and thencooled to −20° C.

A solution of1,1-dimethylethyl-5-(hydroxymethyl)-4-{4-[(trifluoromethyl)oxy]phenyl}-3,6-dihydro-1(2H)-pyridinecarboxylate(P34, 1.69 g) in dry DCM (50 mL) was added dropwise and the reactionmixture was stirred at −20° C. for 30 minutes, then overnight at roomtemperature. HCl 1M was added into the reaction flask and the mixturewas vigorously stirred for 30 minutes; the two phases were separated andthe aqueous layer was basified with NaOH 3N. The basic solution wasextracted with diethyl ether (2 times). The combined organic layers wereconcentrated in vacuo and the residue was taken up with diethyl ether.This solution was washed with saturated NH₄Cl aqueous solution and theaqueous phase was basified with NaOH 3N. The basic solution wasextracted with diethyl ether (2 times). The combined organic layers weredried on anhydrous Na₂SO₄ and the solvent was removed under reducedpressure obtaining the title compound (170 mg).

NMR (¹H, CDCl₃): S ppm 7.36 (d, 2H) 7.16 (d, 2H) 3.39 (d, 1H) 3.05-3.29(m, 3H) 2.64-2.86 (m, 2H) 1.85-2.07 (m, 2H) 1.05-1.13 (m, 1H) 0.96-1.05(m, 1H); MS (m/z): 288 [MH]⁺.

Preparation 36:(1S,6R/1R,6S)-1,1-dimethylethyl-1-(hydroxymethyl)-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate(P36)

To a stirred solution of(1S,6R/1R,6S)-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]hept-1-yl)methanol(170 mg) (P35) in dry DCM (6 mL) under N₂ atmosphere, at 0° C.,di-tert-butyl dicarbonate (129 mg) was added and the reaction mixturewas left stirring at 0° C. for 15 minutes. Saturated NH₄Cl aqueoussolution and DCM were added to the solution and then the organic phasewas separated, dried and the solvent was removed under reduced pressure.The crude was purified by flash-chromatography (eluting withcyclohexane/ethyl acetate from 8:2 to 7:3) to give the title compound(173 mg).

NMR (¹H, CDCl₃): δ ppm 7.35 (d, 2H) 7.17 (d, 2H) 3.73-3.90 (m, 2H)3.09-3.51 (m, 4H) 2.06-2.20 (m, 1H) 1.89-2.06 (m, 1H) 1.51 (s, 9H)1.03-1.10 (m, 1H) 0.93-1.02 (m, 1H).

Preparation 37: 3-methyl 1-(phenylmethyl)4-oxo-1,3-piperidinedicarboxylate (P37)

To a stirred solution of 4-oxo-3-piperidinecarboxylate (5 g) in dry DCM(50 ml), under N₂ atmosphere, TEA (9 mL) was added at rt and then, at 0°C., benzylchloroformate (4.2 mL) was added slowly and stirring wascontinued for 30 minutes at 0° C. and 1 h at RT. The mixture wasquenched at 0° C. with HCl 2N. The aqueous phase was extracted with DCM(2 times) and the combined organic layers were washed with saturatedNaCl aqueous solution, dried and concentrated in vacuo to give the titlecompound (7.5 g).

NMR (¹H, CDCl₃): δ ppm 12.00 (s, 1H) 7.31-7.50 (m, 5H) 5.19 (s, 2H) 4.16(s, 2H) 3.80 (s, 3H) 3.67 (t, 2H) 2.42 (s, 2H)

Preparation 38: 3-methyl 1-(phenylmethyl)4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (P38)

To a stirred solution of 3-methyl 1-(phenylmethyl)4-oxo-1,3-piperidinedicarboxylate (7.5 g) (P37) in dry DMF (80 ml) underN₂ atmosphere at 0° C., NaH 60% on mineral oil (1.13 g) was added. After10 min stirring at 0° C.,1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide(9.64 g) was added and the mixture was stirred for 1 h. The mixture wasthen quenched with saturated NH₄Cl aqueous solution and the phase wasextracted with Et₂O (2 times). The combined organic layers were washedwith saturated NaCl aqueous solution, dried and concentrated undervacuum obtaining the title compound (10 g).

NMR (¹H, CDCl₃): δ ppm 7.34-7.46 (m, 5H) 5.19 (s, 2H) 4.38 (s, 2H) 3.85(s, 3H) 3.72 (t, J=5.31 Hz, 2H) 2.55 (s, 2H); MS (m/z): 424 [MH]⁺

Preparation 39: 3-methyl 1-(phenylmethyl)4-[3-chloro-4-(trifluoromethyl)phenyl]-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P39)

To a stirred solution of 3-methyl 1-(phenylmethyl)4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (3 g)(P38) and [3-chloro-4-(trifluoromethyl)phenyl]boronic acid (1.826 g) indry toluene (37 mL) under N₂ atmosphere at 0° C., Pd(PPh₃)₄ (292 mg)dissolved in absolute EtOH (26 ml), was added followed by Na₂CO₃ 2M (21mL). The reaction mixture was heated to 80° C. for 2 h. Et₂O was thenadded to the solution and the organic phase was separated. The aqueouslayer was extracted with Et₂O and the combined organic phases werewashed with saturated NaCl aqueous solution, dried and concentratedunder vacuum. The crude was purified by flash-chromatography (elutingwith cyclohexane/ethyl acetate from 9:1 to 8:2) to give the titlecompound (3.03 g).

NMR (¹H, CDCl₃): δ ppm 7.43-7.52 (m, 2H) 7.31-7.43 (m, 5H) 7.24 (d, 1H)5.21 (s, 2H) 4.21-4.44 (m, 2H) 3.64-3.77 (m, 2H) 3.55 (s, 3H) 2.51 (s,2H); MS (m/z): 454 [MH]+

Preparation 40: phenylmethyl4-[3-chloro-4-(trifluoromethyl)phenyl]-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P40)

To a stirred solution of 3-methyl 1-(phenylmethyl)4-[3-chloro-4-(trifluoromethyl)phenyl]-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P39, 3.03 g) in dry diethyl ether (60 mL) under N₂ atmosphere, at −20°C., LiAlH₄ (1 M in diethyl ether, 6.25 mL) was added dropwise. Thereaction mixture was left stirring at −20° for 20 minutes then saturatedNH₄Cl aqueous solution and diethyl ether were added to the reactionmixture. The two phases were separated and the aqueous layer wasextracted with diethyl ether. The combined organic phases were washedwith brine, dried on anhydrous Na₂SO₄ then the solvent was removed underreduced pressure, obtaining a crude product that was purified byflash-chromatography (eluting with cyclohexane/ethyl acetate from 9:1 to7:3) to give the title compound (700 mg).

NMR (¹H, CDCl₃): δ ppm 7.30-7.56 (m, 8H) 5.21 (s, 2H) 4.25 (s, 2H)3.94-4.08 (m, 2H) 3.72 (t, 2H) 2.44 (s, 2H); MS (m/z): 426 [MH]+

Preparation 41: (1S,6R/1R,6S)-phenylmethyl6-[3-chloro-4-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P41)

To a stirred solution of CH₂I₂ (13.25 g) in dry DCM, under N₂atmosphere, at 0° C., ZnEt₂ 1M in hexane (24 mL) was added and after 30min the reaction mixture was cooled to −20° C. Phenylmethyl4-[3-chloro-4-(trifluoromethyl)phenyl]-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(700 mg) (P40) in dry DCM, was added (total amount of DCM 60 ml); thesolution was stirred for 30 min at −20° C. and at RT overnight. Thereaction mixture was quenched with HCl 0.1M and stirred for 30 min. Theorganic layer was separated, washed with saturated NaCl aqueoussolution, dried and concentrated in vacuo. The crude was purified byflash-chromatography (eluting with cyclohexane/ethyl acetate from 9:1 to7:3) to give 430 mg of impure title compound in a mixture withphenylmethyl4-[3-chloro-4-(trifluoromethyl)phenyl]-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(ratio=2:1 form NMR analysis).

MS (m/z): 440 [MH]⁺, 426 [MH]+

Preparation 42: 3-methyl 1-(phenylmethyl)4-(2-naphthalenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P42)

The title compound was prepared according to a similar procedure to thatpreviously described for Preparation 33 in 2.28 g yield starting from3-methyl 1-(phenylmethyl)4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-piperidinedicarboxylate (3 g,P38).

NMR (¹H, CDCl₃): δ ppm 7.08-7.90 (m, 12H) 5.23 (s, 2H) 4.28-4.48 (m, 2H)3.64-3.84 (m, 2H) 3.49 (s, 3H) 2.53-2.72 (bs, 2H)

Preparation 43: phenylmethyl5-(hydroxymethyl)-4-(2-naphthalenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P43)

The title compound was prepared according to a similar procedure to thatpreviously described for Preparation 34 in 1.275 g yield starting from3-methyl 1-(phenylmethyl)4-(2-naphthalenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (2.28 g,P42).

NMR (¹H, CDCl₃): δ ppm 7.21-7.91 (m, 12H) 5.23 (s, 2H) 4.20-4.37 (m, 2H)4.00-4.18 (m, 2H) 3.64-3.83 (m, 2H) 2.43-2.63 (m, 2H)

Preparation 44:(1S,6R/1R,6S)-phenylmethyl-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P44)

Step a)

An impure batch of Phenylmethyl(1R,6S)-1-(hydroxymethyl)-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(850 mg) was prepared starting fromphenylmethyl-5-(hydroxymethyl)-4-(2-naphthalenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(1.275 g) (P43) according to a similar procedure to that previouslydescribed for Preparation 41.

Step b)

The title compound was prepared starting from Phenylmethyl(1R,6S)-1-(hydroxymethyl)-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(850 mg) according to a similar procedure to that described for E14,Step A, in 600 mg yield.

NMR (¹H, CDCl₃): δ ppm 7.04-7.90 (m, 12H) 5.20 (t, 2H) 4.01 (m, 1H)3.78-3.92 (d, 1H) 3.44-3.56 (m, 2H) 3.16-3.24 (m, 1H) 3.10 (s, 3H)2.98-3.03 (m, 1H) 2.16-2.30 (m, 1H) 1.95-2.12 (m, 1H) 1.16-1.25 (m, 1H)1.01-1.12 (m, 1H); MS (m/z): 402 [MH]+

Preparation 45:([3-(3-chloro-4-fluorophenyl)-3-buten-1-yl]oxy)(1,1-dimethylethyl)diphenylsilane(P45)

The title compound was prepared according to a similar procedure to thatpreviously described for Preparation 13 in 3.624 g yield starting from[(3-bromo-3-buten-1-yl)oxy](1,1-dimethylethyl)diphenylsilane (3.890 g,P12).

NMR (¹H, CDCl₃): δ ppm 7.00-7.65 (m, 13H) 5.29 (m, 1H) 5.11 (m, 1H) 3.74(t, 2H) 2.70 (t, 2H) 1.02 (s, 9H)

Preparation 46:dimethyl-2-(3-chloro-4-fluorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate(P46)

The title compound was prepared in 2.61 g yield starting from{[3-(3-chloro-4-fluorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsilane(P45, 3.624 g) and from dimethyl diazenylpropanedioate (1.98 g)according to a similar procedure described for Preparation 14.

NMR (¹H, CDCl₃): δ ppm 7.25-7.62 (m, 1H) 7.04-7.11 (m, 1H) 6.99 (t, 1H)3.82 (s, 3H) 3.49-3.59 (m, 1H) 3.33-3.46 (m, 4H) 2.10-2.26 (m, 2H)1.76-1.87 (m, 1H) 1.59-1.66 (m, 1H) 0.99-1.10 (m, 9H); MS (m/z): 569[MH]⁺

Preparation 47:methyl-1-(aminocarbonyl)-2-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)cyclopropanecarboxylate(P47)

The title compound was prepared in 1.05 g yield starting from dimethyl2-(3-chloro-4-fluorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate(2.61 g, P46) according to a similar procedure to that previouslydescribed for Preparation 15.

NMR (¹H, CDCl₃): δ ppm 8.19 (s, 1H) 7.34 (d, 1H) 7.14-7.22 (m, 1H) 7.10(t, 1H) 5.76 (s, 1H) 3.42-3.66 (m, 2H) 3.06-3.26 (m, 3H) 1.89-2.35 (m,4H); MS (m/z): 316 [MH]⁺

Preparation 48: (1S,6R/1R,6S)-methyl6-(3-chloro-4-fluorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(48)

The title compound was prepared in 360 mg yield starting from methyl1-(aminocarbonyl)-2-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)cyclopropanecarboxylate(1.05 g, P47) according to a similar procedure described for Preparation16.

NMR (¹H, CDCl₃): δ ppm 7.42 (dd, 1H) 7.21-7.27 (m, 1H) 7.10 (t, 1H) 5.83(s, 1H) 3.53 (s, 3H) 2.85-3.42 (m, 2H) 2.33-2.48 (m, 1H) 2.24-2.32 (m,1H) 2.09-2.22 (m, 1H) 1.99 (d, 1H); MS (m/z): 298 [MH]⁺

Preparation 49: (1S,6R/1R,6S)-1,1-dimethylethyl6-(3-chloro-4-fluorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P49)

The title compound was prepared in 184 mg yield starting from(1S,6R/1R,6S)-methyl-6-(3-chloro-4-fluorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(360 mg, P48) according to a similar procedure described for Preparation5 (Method C).

NMR (¹H, CDCl₃): δ ppm 7.37 (dd, 1H) 7.16-7.24 (m, 1H) 7.09 (t, 1H)3.72-3.89 (m, 2H) 3.26-3.46 (m, 3H) 3.11-3.26 (m, 1H) 1.90-2.16 (m, 2H)1.51 (s, 9H) 1.01 (dd, 2H)

Preparation 50:(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P50)

The title compound was prepared in 164 mg yield starting from(1S,6R/1R,6S)-1,1-dimethylethyl6-(3-chloro-4-fluorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(184 mg, P49) according to a similar procedure to that described forExample 14, Step A.

NMR (¹H, CDCl₃): δ ppm 7.38 (d, 1H) 7.14-7.23 (m, 1H) 7.07 (t, 1H) 3.86(s, 1H) 3.70 (d, 1H) 3.27-3.42 (m, 2H) 3.15 (s, 3H) 3.00-3.11 (m, 1H)2.86 (d, 1H) 1.92-2.13 (m, 2H) 1.44-1.54 (m, 9H) 0.90-1.03 (m, 2H)

Preparation 51: 1,1-dimethylethyl(1R,6S1/S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P51)

To a stirred solution of(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P5, 0.1 g) in dry DMF (2 mL), under a nitrogen atmosphere, sodiumhydride (60% in mineral oil, 13 mg) was added and the stirring continuedfor 5 min. After this period of time iodoethane (28 μL) was added andthe reaction mixture was stirred overnight at RT. An additional amountof sodium hydride (3 mg) and iodoethane (28 μL) were added and themixture was stirred for further 4 h. Aqueous saturated NaHCO₃ solutionwas added and the mixture was extracted with DCM. The organic phase wasconcentrated under vacuum and the crude product was purified byflash-chromatography (eluting with cy/EA from 1/0 to 8/2) to give thetitle compound (79 mg).

NMR (¹H, MeOH-d₄): δ 7.48 (s, 1H) 7.35 (d, 1H) 7.15 (d, 1H) 3.7-3.4 (m,2H) 3.3 (m, 3H) 3.15 (m, 2H) 2.85 (d, 1H) 2.0 (m, 2H) 1.5 (s, 9H) 1.1(t, 3H) 0.95 (m, 2H);

MS (m/z): 422 [M+Na]⁺

Preparation 52: 1,1-dimethylethyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate(P52)

To a stirred solution of diisopropylamine (0.77 ml) in dry THF (12 mL)at −78° C. and under a nitrogen atmosphere, butyl lithium (2.5M inhexane, 2.2 ml) was added and the reaction mixture was stirred at −78°C. for 15 minutes. DMPU (1.8 ml) and a solution of 1,1-dimethylethyl4-oxo-1-piperidinecarboxylate (1 g) in THF (5 ml) were added and thereaction mixture was stirred at −78° C. for 2 hours. Then a solution ofN-phenyl-bis(trifluoromethanesulfonimide) (1.97 g) in THF (6 ml) wasadded and stirring was continued at 0° C. for 9 hours and at roomtemperature per 16 h. The solvent was removed under reduced pressure andthe crude purified by flash-chromatography (eluting with ethylacetate/cycloexane 2:8) to give 1.375 g of the title compound.

NMR (¹H, CDCl₃): δ 5.79 (br. s., 2H) 4.07 (m, 2H) 3.65 (m, 2H) 2.47 (m,2H) 1.50 (s, 9H).

Preparation 53: 1,1-dimethylethyl4-(3,4-dichlorophenyl)-3,6-dihydro-1(2H-pyridinecarboxylate (P53)

To a mixture of 1,1-dimethylethyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate(P52, 500 mg), 3,4-dichlorophenylboronic acid (330 mg) and Pd(PPh₃)₄ (50mg) under nitrogen, toluene (6.5 mL), ethanol (5 mL) and Na₂CO₃ (2M, 5mL) were added in sequence. The mixture was stirred at 80° C. for 2hours then the reaction mixture was allowed to reach room temperature.Saturated NH₄Cl (30 mL) was poured into the solution and the mixture wastransferred in a separator funnel. The mixture was extracted with ethylacetate (3×40 mL), the combined organic phases were dried on anhydrousNa₂SO₄ and the solvent evaporated obtaining a crude product that waspurified by flash-chromatography (eluting with ethyl acetate/cycloexane1:9) to give the title compound (400 mg).

MS (m/z): 328 [MH]+

Preparation 54: 3-(1,1-dimethylethyl) 7-ethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-3,7-dicarboxylateand 1,1-dimethylethyl4-(3,4-dichlorophenyl)-6-[2-(ethyloxy)-2-oxoethyl]-3,6-dihydro-1(2m-pyridinecarboxylate(P54)

To a solution of 1,1-dimethylethyl4-(3,4-dichlorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (P53, 825mg) in DCE (10 ml) was added rhodium acetate dimer (110 mg). The mixturewas heated at 40° C. and a solution of ethyl diazoacetate (0.31 ml) inDCE (2.5 ml) was added with a syringe pump in 4 h maintaining theinternal temperature at 50° C. during the addition. The solvent wasremoved under reduced pressure and the crude purified byflash-chromatography (eluting with ethyl acetate/cycloexane 2:8) to give170 mg of a mixture of title compounds.

MS (m/z): 414 [MH]⁺

Preparation 55: 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylateand 1,1-dimethylethyl4-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P55)

To a stirred solution of (1,1-dimethylethyl) 7-ethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-3,7-dicarboxylateand 1,1-dimethylethyl4-(3,4-dichlorophenyl)-6-[2-(ethyloxy)-2-oxoethyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(P54, obtained following an analogous procedure to that previouslydescribed for P54, 38 mg) in dry toluene (1 mL) under N₂ atmosphere, at−20° C., LiAlH₄ (1M in diethyl ether, 0.37 mL) was added dropwise. Thereaction mixture was left stirring at −20° for 1 hour then saturatedNH₄Cl was added and the products extracted with ethyl acetate. Thephases were separated, the organic phase was dried over Na₂SO₄ and thesolvent was removed under reduced pressure to give a mixture of thetitle compounds as crude (30 mg).

MS (m/z): 372 [MH]⁺

Preparation 56: 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylateand 1,1-dimethylethyl4-(3,4-dichlorophenyl)-6-[2-(methyloxy)ethyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(P56)

To a stirred solution of 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylateand 1,1-dimethylethyl4-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(P55, 30 mg) in dry DMF (1 mL) under nitrogen atmosphere, at 0° C., NaH(60% on mineral oil, 5 mg) was added and the mixture stirred for 30minutes at 0° C. Methyl iodide (10 μL) was added and the reaction wasallowed to reach room temperature and stirred for 2 h. Chilly water wasadded and the product extracted with ethyl acetate. The organic phasewas washed with brine, dried over Na₂SO₄, and the solvent evaporatedunder reduced pressure to give a mixture of the title compounds as crudematerial (35 mg).

MS (m/z): 386 [MH]+

Preparation 57: 3-(1,1-dimethylethyl) 1-ethyl(1S,6R/1R,6S)-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dicarboxylate(P57)

Step a)

A 50-L Jacketed laboratory reactor was charged with lithiumtert-butoxide (1.85 Kg, 23.1 mol, 3 eq) and 1-methyl-2-pyrrolidinone(19.1 Kg). The mixture was stirred for −30 min, and the resultingsolution was charged into a pressure vessel for later use.

A clean, 50-L Jacketed laboratory reactor was charged with a solution of1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate intoluene (prepared in a similar manner to that described in P72,containing P72 in a theoretical amount of 3.09 Kg) through a 0.45 μmMeissner™ in-line filter. The lines and filter were washed with a smallamount of toluene. The toluene was completely removed from the reactionmixture by distillation under reduced pressure. 1-methyl-2-pyrrolidinone(16.0 Kg) was added and the resulting solution cooled to 20° C., andheld overnight due to time constraints. Chloroiodomethane (4.15 Kg, 3.05eq) was charged into the reactor, and the resulting slurry was cooled to−4° C. A portion of the previously prepared solution of lithiumtert-butoxide in 1-methyl-2-pyrrolidinone (16.9 Kg, −2.4 eq of base) wasadded over 28 min, and the resulting solution was warmed to 19° C. andstirred for 80 min. Acetic acid (0.69 Kg, 1.5 eq) was added all at once,followed by a slow addition of water (8.5 Kg) over ˜10 min. The mixturewas stirred for −5 min, and water (13.1 Kg) was added over 18 min. Theresulting slurry was cooled to 11° C. and held for 100 min. The solidswere collected by filtration. Water (3.9 Kg) and methanol (9.21 Kg) werecharged into the reactor to rinse it, and the resulting aqueous methanolsolution was used to wash the product cake. The resulting yellow solidswere dried to a constant weight in a 55° C. vacuum oven to provide 2.57Kg of the title compound in 81% yield.

NMR (¹H, CDCl₃): δ 7.32 (2H, m), 7.08 (1H, m), 6.62 (1H, br m), 5.13(1H, br m), 4.24 (1H, br m), 3.76 (3H, br m), 2.29 (1H, m), 1.56 (1H,m), 1.49 (9H, s), 0.91 (3H, br m)

Step B) (Recrystallization)

A 50-L jacketed laboratory reactor was charged with(±)-3-(1,1-dimethylethyl) 1-ethyl(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dicarboxylate(P57, 4.40 Kg, 11.0 moles, 1 eq) and heptane (15.1 Kg, 22.1 L, 5 vol).The resulting slurry is heated to approximately 80° C. and filtered intoa clean 50-L jacketed laboratory reactor. The filter and lines wererinsed with heptane (3.0 Kg, 4.4 L, 1 vol) and the rinse was combinedwith the filtrate. The solution was heated to 80° C. and then cooled to22° C. over 107 min. No crystals had formed so a small aliquot was takenout. Crystals formed spontaneously in the aliquot and were returned tothe reactor which caused rapid crystallization. The slurry was heatedback to 80° C. and cooled to 22° C. over 105 min. During the cool, asmall aliquot was pulled at 52° C. The wall of the vial holding thealiquot was scratched to initiate crystallization and the resultingslurry was combined with the bulk solution when its temperature hadreached 47° C. The solids were collected by filtration, the reactor wasrinsed with heptane (3.0 Kg, 4.4 L, 1 vol), and the rinse was used towash the filter cake. The solids were dried to a constant weight in a50-60° C. vacuum oven to provide 2.954 Kg, 67% yield, of title compoundas an off-white solid.

NMR (¹H. CDCl₃): δ 7.35 (2H, m), 7.27 (CDCl₃), 7.11 (1H, m), 6.65 (1H,br m), 5.16 (1H, br m), 4.27 (1H, br m), 3.79 (3H, br m), 2.32 (1H, m),1.59 (1H, m), 1.52 (9H, s), 0.94 (3H, br m)

Preparation 58: 1,1-dimethylethyl(1S,6R/1R,6S)-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P58)

3-(1,1-dimethylethyl) 1-ethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-4-ene-1,3-dicarboxylate(P57, 39.97 g, 0.9694 mol, 1 eq) was dissolved in THF (80 mL, 2 vol). Asolution of 2M LiBH₄ in THF (120 mL, 0.242 mol, 2.5 eq) was added andthe resulting solution was cooled with a room temperature water bath.Ethanol (28.5 mL, 0.485 mol, 5 eq) was added over 65 min. The reactionwas stirred for 40 min, and heptane (200 mL, 5 vol) was added. Water wasadded (10 mL, 550 mole, 5.7 eq) over −10 min, and the resulting slurrywas stirred for 15-20 min. More water was added (200 mL, 5 vol), themixture was stirred for 15 min, and the layers were allowed to settled,and separated. The organic layer was washed with water (200 mL, 5 vol),and then filtered through Whatman brand #2 filter paper and concentratedin vacuo. The resulting oil was dried in a 60° C. vacuum oven for −72 hto provide 29.48 g, 82% yield, of title compound as a glassy solid.

NMR (¹H, CDCl₃): δ 7.38 (2H, br m), 7.15 (1H, br m), 6.60 (1H, br m),5.12 (1H, br m), 4.24 (1H, br m), 3.38 (2H, br m), 3.29 (1H, br m), 1.51(10H, br m), 1.30 (1H br m).

Preparation 59: 1,1-dimethylethyl(1S,6R/1R,6S)-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P59)

1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P58, 28.4 g, 76.7 mmol) was dissolved in DMSO (225 ml). The solutionwas then treated with potassium hydroxide (powder, 17.2 g, 0.3 mol) andstirred for 15 min. Iodomethane (9.5 ml, 0.15 mol) was added dropwiseover 15 min and the reaction stirred for 90 min at room temperature. Itwas then quenched with water (115 ml) and MTBE (250 ml) and stirred for1 h. The phases were then separated and the top (organic) phase washedwith water (115 ml) and concentrated in vacuo to give the title compoundas an oil (32 g crude weight).

NMR (¹H, CDCl₃): δ 7.40 (1H, d, J=4 Hz), 7.37 (1H, d, J=8 Hz), 7.15 (1H,dd, J=8, 4 Hz), 6.55 (1H, br m), 5.08 (1H, br m), 4.19 (1H, br m), 3.27(1H, br m), 3.10 (3H, br s), 3.04 (1H, br m), 2.96 (1H, br m), 1.49 (9H,br s), 1.42 (1H, d, J=4 Hz), 1.28 (1H, br m).

MS (m/z): 328 [M-t-Bu+2H]+

Preparation 60: 1,1-dimethylethyl(1S,6R)-6-3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-one-3-carboxylate(P60)

1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P59, 36 grams, 9.4 mmol) was dissolved in 370 mL (5% IPA in heptane)and the two enantiomers separated by chiral HPLC. Rt=5.7 min [Columnused for processing: Chiralpak AD, 20 um, 20×250 mm, (ambient temp.)Processing parameters: Flow: 15 mL/min; Detection: 225 & 280 nm; Feedstock: 100 mg/mL]

After the solvent was evaporated, the product was isolated as an oil(16.2 g, optical purity, 99.2%).

Preparation 61: 3-(3,4-dichlorophenyl)-3-buten-1-ol (P61)

In a round-bottomed flask equipped with mechanical stirrer, under anargon atmosphere, 3,4-dichlorophenylboronic acid (128 g, 672 mmol) and3-bromo-3-buten-1-ol (78 g, 517 mmol) were dissolved in toluene (1230ml) and ethanol (492 ml). To this solution,tetrakis(triphenylphosphine)palladium(0) (29.8 g, 25.8 mmol) was addedfollowed by sodium carbonate 2M aqueous solution (517 ml, 1033 mmol).The resulting mixture was heated at an internal temperature of 75° C.After 30 minutes, a thick precipitate formed. After 1 h, water (50 ml)was added to make the solid re-dissolved and the reaction mixture turnedslightly yellow opalescent. At 3 h the reaction was worked-up. Flask wascooled down to room T (a precipitate was formed) and the mixture wastaken up with aqueous NaHCO₃ sat. solution (468 mL), water (468 mL) andAcOEt (468 mL). At addition of water solid dissolved; phases wereseparated and aqueous one back extracted with AcOEt (2×936 mL). Combinedorganics were dried (Na₂SO₄), concentrated under vacuum to give crudematerial (200 g) as black thick oil. This oil was purified by silica gelflash chromatography, eluting with cyclohexane/AcOEt from 8/2 to 7/3.Evaporation of solvent afforded the title compound (73 g), as dark thickoil.

NMR (¹H, CDCl₃): δ ppm 7.51 (d, 1H), 7.41 (d, 1H), 7.26 (dd, 1H),5.34-5.53 (m, 1H), 5.02-5.29 (m, 1H), 3.60-3.95 (m, 2H), 2.57-2.94 (m,2H), 1.50 (t, 1H)

Preparation 62: 3-(3,4-dichlorophenyl)-3-buten-1-yl methanesulfonate(P62)

In a round-bottomed flask, 3-(3,4-dichlorophenyl)-3-buten-1-ol (P61, 73g, 336 mmol) was dissolved in DCM (900 ml) to give a yellow solution.Then triethylamine (69.9 ml, 504 mmol) was added keeping the internaltemperature below +5° C. with an ice bath. Methanesulfonyl chloride(36.7 ml, 471 mmol) was then added dropwise in 30 min. keeping theinternal temperature below +5° C. with an ice bath. The mixture wasallowed to reach room temperature while stirring. After 3 h, thereaction mixture (suspension) was quenched by careful addition ofaqueous ammonium chloride sat. solution (400 ml) keeping the internaltemperature below +10° C. with an ice bath. At the end of the additionthe pH of the aqueous phase was nearly 1. The two layers were separated.The aqueous layer was back-extracted with DCM (3×300 mL). The combinedorganic layers were washed with water (2×200 mL), dried (Na₂SO₄), andevaporated to give a crude product (101 g) that was purified over asilica gel pad (1000 g) eluting with cyclohexane/EtOAc from 9/1 to 1/1to afford the title compound (90.8 g) as a dark yellow oil.

NMR (¹H, CDCl₃): δ ppm 7.49 (d, 1H), 7.44 (d, 1H), 7.24 (dd, 1H), 5.46(d, 1H), 5.25 (d, 1H), 4.32 (t, 2H), 2.98 (s, 3H), 2.93 (t, 2H)

HPLC (walk-up): Rt=5.37 min

Preparation 63: dimethyl2-(3,4-dichlorophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopropanedicarboxylate(P63)

In a round-bottomed flask, 3-(3,4-dichlorophenyl)-3-buten-1-ylmethanesulfonate (P62, 90.8 g, 308 mmol) was dissolved in chlorobenzene(200 ml) to give a green solution. Rhodium acetate dimer (6.80 g, 15.38mmol) was added. The suspension was warmed to an internal temperature of+65° C. and dimethyl diazopropanedioate (78 g, 492 mmol, for a referenceprocedure of preparation see Synthetic Communication 1987, 17 (14),1709-1716) dissolved in chlorobenzene (150 ml) was added dropwise(during 2.5 hrs), keeping the internal temperature below 65-67° C. Atthe end of the addition, the mixture was cooled to room temperature. Itwas diluted with DCM (300 ml) and filtered over a celite pad to separatethe catalyst.

The solution was evaporated in vacuo to ⅓ of the volume and the crude(277 g) purified over a silica pad (silica gel 1.3 Kg) eluting withcyclohexane/ethyl acetate from 7/3 to 1/1 to afford the title compound(128.25 g).

NMR (¹H, CDCl₃): δ ppm 7.41 (d, 1H), 7.39 (d, 1H), 7.15 (dd, 1H),4.08-4.22 (m, 1H), 3.94-4.06 (m, 1H), 3.85 (s, 3H), 3.48 (s, 3H), 2.95(s, 3H), 2.42 (dt, 1H), 2.21 (d, 1H), 1.89-2.03 (m, 1H), 1.82 (d, 1H)

HPLC (walk-up): Rt=5.15 min

Preparation 64: methyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P64)

In a 5 L Parr reactor, dimethyl2-(3,4-dichlorophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}1,1-cyclopropanedicarboxylate(P63, 158 g, 372 mmol) was dissolved in ammonia 2M in methanol (3000 ml)to give a yellow solution. The solution was warmed to +75° C. and theresulting mixture was stirred at this temperature overnight (internalpressure=2 atm). After 24 hrs, reaction was complete. The solution wasconcentrated to obtain a residue that was mixed with a residue (89.3 g)coming from an analogous preparation performed on another batch of2-(3,4-dichlorophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopropanedicarboxylate.The solvent was evaporated to obtain a crude oil (280 g). To this oil,AcOEt (5 L) and 1M aqueous HCl (2.5 L) were added and the mixture wasvigorously stirred for 30 min in a 10 L reactor.

A diluted suspension (a mixture of organic phase, aqueous phase andsolid) was obtained. The solid was filtered, washed with ethyl acetateand dried to afford a first batch of title compound (54.9 g).

The organic and aqueous layers were separated. The organic phase wasthen washed with aqueous HCl 1M (2 L), dried (Na₂SO₄) and concentratedto 1/10 of the volume. A solid precipitated out. It was filtered, washedwith diethyl ether (150 ml) and dried under vacuum to afford a secondbatch of title compound (34.4 g). The mother liquours of filtration wereconcentrated in vacuo to obtain a brown oil. This residue was trituratedwith ethyl ether (1×50 mL). The resulting solid was filtered, washedwith cold ethyl ether and dried to give a third batch of title compound(7.27 g) as a off white solid.

The mother liquours were concentrated and chromatographed on Biotage 75M(silica gel) eluting with AcOEt to give a solid that was triturated inethyl ether (35 ml) to give a fourth batch of title compound (6.2 g).

An overall amount of 102.7 g of product was thus obtained.

NMR (¹H, CDCl₃): δ ppm 7.47 (d, 1H), 7.41 (d, 1H), 7.20 (dd, 1H), 5.73(br. s., 1H), 3.54 (s, 3H), 3.07-3.41 (m, 2H), 2.32-2.45 (m, 1H), 2.28(d, 1H), 2.17 (d, 1H), 1.93 (d, 1H)

Preparation 65: 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P65)

Step a)

In a round-bottomed flask, methyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P64, 90 g, 286 mmol) was dissolved in THF (1450 ml) to give a greysuspension. Borane tetrahydrofuran complex 1M (1633 ml, 1633 mmol) wasadded dropwise keeping the internal temperature below +5°. The resultingmixture was gently refluxed for 7 hrs. The mixture was cooled to +3° C.and quenched by careful addition of methanol (200 ml); then aqueous HCl6M (450 ml) was added keeping the internal temperature below +6° C. Themixture was stirred at room temperature for 5 h. The acidic solution wasconcentrated under vacuum to remove THF, then water (900 ml) was added.The pH of the final solution was nearly 1. This solution was washed withethyl ether (2×200 ml). The aqueous solution was basified by portionwiseaddition of potassium carbonate until pH 8-9, then THF (1200 ml) wasadded and the resulting mixture used directly in the next step.

Step b)

A round-bottomed flask was charged with the mixture coming from step a)(approximately 2700 ml, pH=8-9). Di-tert-butyl dicarbonate (80 ml, 343mmol) was added portionwise at room temperature and the mixture wasstirred overnight. The organic and aqueous layers were separated. Theaqueous layer was back-extracted with ethyl acetate (3×600 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated to obtain acrude oil (165 g) that was purified over a silica pad (silica gel 1500g), eluting with cyclohexane/ethyl acetate 8/2 to give the titlecompound (110 g) as a foamy colourless oil.

NMR (¹H, CDCl₃): δ ppm 7.39-7.42 (m, 1H), 7.37 (d, 1H), 7.17 (d, 1H),3.73-3.90 (m, 2H), 2.99-3.49 (m, 4H), 1.91-2.13 (m, 2H), 1.48 (s, 9H),0.92-1.07 (m, 2H).

HPLC (walk-up): Rt=6.12 min

Preparation 66: 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P66)

In a 1 L round-bottomed flask, 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P65, 47.56 g, 128 mmol) was dissolved in THF (800 ml) to give acolourless solution. Sodium hydride (10.22 g, 256 mmol) was addedkeeping the internal temperature at 0° C. After 30 min, MeI (15.98 ml,256 mmol) was added dropwise at the same temperature. The resultingmixture was stirred overnight at room temperature.

The mixture was quenched by dropwise addition of aqueous NaHCO₃ sat.(500 ml) keeping the internal temperature below +15° C. The resultingsuspension was filtered, the solid was dissolved with water (200 ml).The two phases were separated and the aqueous phase was extracted withethyl acetate (3×200 ml). The combined organic layers, dried (Na₂SO₄),were evaporated to give crude material (54 g) that was purified bysilica gel chromatography, eluting with cyclohexane/ethyl acetate from95/5 to 75/25 to give the title compound as a colourless oil (42.33 g).

NMR (¹H, CDCl₃): δ ppm 7.40-7.43 (m, 1H), 7.36 (d, 1H), 7.16 (d, 1H),3.85 (d, 1H), 3.67 (d, 1H), 3.26-3.40 (m, 2H), 3.14 (s, 3H), 2.97-3.10(m, 1H), 2.81-2.91 (m, 1H), 1.90-2.07 (m, 2H), 1.49 (s, 9H), 0.91-1.02(m, 2H)

HPLC (walk-up): Rt=7.15 min

Preparation 67: dimethyl(2S)-2-(3,4-dichlorophenyl)-2(2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopropanedicarboxylateand dimethyl(2R)-2-(3,4-dichlorophenyl)-2-(2-[(methylsulfonyl)oxy]ethyl}-1,1-cyclopropanedicarboxylate(P67)

3-(3,4-dichlorophenyl)-3-buten-1-yl methanesulfonate (2.0 g, 6.78 mmol)and Rh2-[(S)-4-Cl-nttl]-4 (preparation of the catalyst described inHelv. Chem. Act., vol. 88 (2005), p. 216 and ss.) (0.105 g, 0.066 mmol)were dissolved in chlorobenzene (10 ml) at 25° C. A solution of dimethyldiazopropanedioate (1.7 g, 10.75 mmol) in chlorobenzene (10 ml) wasadded dropwise in 2 h.

The chlorobenzene was evaporated and the residue chromatographed oversilica (230-400 Mesh) eluting with cyclohexane/AcOEt 8/2, 7/3 to affordthe title compound (2.65 g).

NMR (¹H, CDCl₃): δ ppm 7.41 (d, 1H), 7.39 (d, 1H), 7.15 (dd, 1H),4.08-4.22 (m, 1H), 3.94-4.06 (m, 1H), 3.85 (s, 3H), 3.48 (s, 3H), 2.95(s, 3H), 2.42 (dt, 1H), 2.21 (d, 1H), 1.89-2.03 (m, 1H), 1.82 (d, 1H)

Chiral HPLC (Column: Chiralpak AD-H (25×0.46 cm); Mobile phase:n-Hexane/Ethanol 70/30% v/v; Flow rate: 1.0 ml/min; DAD:210-340: Enant1(Rt=9.6 min)/Enant2 (Rt=11.7 min)=60/40 area %

Preparation 68: 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-4-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate(P68)

1,1-dimethylethyl4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate(P22, two batches prepared in an analogous manner to that previouslydescribed for P22, 260 mg) were dissolved in DCM (5 mL). It was added at−20° C. to a suspension obtained by addition of diethylzinc 1.0M inhexane (4.19 mL) to a solution of diiodomethane (0.676 mL) in DCM (10mL). The suspension was stirred at room temperature overnight. Thereaction mixture was then quenched with 20 mL of a saturated solution ofNH₄Cl and the two phases were stirred for 30 min. The organic layer waswashed with brine (20 mL), dried and concentrated. Purification bychromatography on silica gel eluting with a gradient 540% ethylacetate/cyclohexane afforded 75 mg of a colourless oil.

NMR (¹H, CDCl₃): δ 7.40-7.42 (m, 1H), 7.38 (d, 1H), 7.17 (dd, 1H),3.39-3.48 (m, 2H), 3.20-3.27 (m, 1H), 2.44 (m, 1H), 2.06-2.16 (m, 1H),1.81-1.91 (m, 1H), 1.61-1.69 (m, 1H), 1.47-1.50 (s, 9H), 1.24-1.28 (d,3H), 0.84-0.94 (m, 2H).

Preparation 69: 1,1-dimethylethyl(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(methylsulfonyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate(P69)

1,1-dimethylethyl(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P5, 132 mg) and triethyl amine (74 μL) were dissolved in DCM (5 mL).Methanesulfonyl chloride (38 μL) was added at room temperature. Afterovernight stirring, DCM and NH₄Cl saturated solution were added. Theorganic solvent was evaporated obtaining the title compound (140 mg).

NMR (¹H, CDCl₃): δ 7.4 (m, 2H) 7.1 (d, 1H) 3.9 (d, 2H) 3.75 (m, 1H) 3.7(s, 2H) 3.4 (m, 2H) 2.9 (m, 3H) 1.7 (m, 1H) 1.5 (s, 9H) 1.1-1.2 (dd,2H); MS (m/z): 450 [MH]+

Preparation 70:1-(1,1-dimethylethyl) 3-ethyl4-oxo-1,3-piperidinedicarboxylate (P70)

To a suspension of 3-ethylcarboxylate-4-piperidone hydrochloride (5 kg,24.08 moles, Alfa Aesar) in heptane (12.7, kg) was charged triethylamine(7.25 kg, Alfa Aesar) at room temperature and the suspension was thenstirred for 15 minutes. Di-tert-butyldicarbonate (6.3 kg, 28.89 moles,1.2 eq., Alfa Aesar) was then added to the reaction over 20 minutes as asolution in heptane (4.1 Kg) at room temperature. The reaction wasstirred at room temperature for approximately 40 min. Then water (25 L)was charged to the reaction at room temperature and stirred for 15minutes. The layers are then allowed to separate and the aqueous layerremoved. The organic layer was then washed with 1N HCl (25 L) and water(22 L). The resulting organic layer was then concentrated to an oil byvacuum distillation, with a jacket temperature of 20° C. Onceconcentrated to an oil, ethanol (13.7 kg)/water (17.5 kg) was thencharged to the reaction and warmed to 50° C. Once reaction temperaturehas stabilized, the reaction is then cooled to −10° C. at a rate of0.25° C./min. The reaction is held at −10° C. for greater than 6 hours.The resulting solids are then filtered, and the filtrate used to rinsethe reactor and wash the filter cake. The recovered solids are thendried at room temperature under full vacuum with a N₂ bleed. Isolated6354 grams of title compound (97% yield).

NMR (¹H, DMSO-d6): δ ppm 1.13-1.30 (m, 3H) 1.40 (s, 9H) 2.32 (t, J=5.98Hz, 2H) 3.48 (t, J=5.98 Hz, 2H) 3.95 (s, 2H) 4.21 (q, J=7.08 Hz, 2H)

Preparation 71: 1-(1,1-dimethylethyl) 3-ethyl4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate(P71)

1-(1,1-Dimethylethyl) 3-ethyl 4-oxo-1,3-piperidinedicarboxylate (P70,380.48 g, 1.40 moles) was dissolved in toluene (2.97 Kg). The solutionwas stirred for 10 mins and then cooled to −7° C. and then treated withN,N-diisopropylethylamine (271.56 g, 2.10 mol) while maintaining thereaction below −7° C. After stirring the reaction mixture forapproximately 10 minutes, trifluoromethanesulfonic anhydride (436.29 g,1.55 mol) was added while maintaining the temperature below 5° C. Thereaction mixture was stirred at 1° C. for 31 minutes.

HPLC: Rt=2.69 min (HPLC instrument Agilent 1100 Series analysisperformed on a Agilent Zorbax SB C18 (50×3.0 mm, 1.8 um), mobile phase:water:acetonitrile:TFA (0.05%), gradient from 0 to 95% in 2.5 min, holdfor 0.2 min, then re-equilibrate; T=60° C.; flow=1.5 mL/min)

Preparation 72: 1-(1,1-dimethylethyl) 3-ethyl4-(3,4-dichlorophenyl)-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (P72)

The 1-(1,1-dimethylethyl) 3-ethyl4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylatesolution in toluene (coming from preparation described for P71) wascooled to approximately −5° C. Next N,N-diisopropylethylamine (288.10 g,2.23 mol), water (376.20 g), triphenylphosphine (27.52 g, 0.105 mol),and palladium (II) acetate trimer (7.88 g, 0.0117 mol) were added. Thereaction mixture was warmed to 21° C. and stirred for 1 hour. Followingthe addition of 3,4-dichlorophenylboronic acid (268.80 g, 1.41 mol), thereaction mixture was heated to 70° C. and stirred for 48 minutes(temperature briefly reached 87.4° C. while heating). The reaction wascooled to −6.4° C. followed by the addition of sodium hydroxide (1N,3286 g) while maintaining the reaction temperature below 5° C. Next, thereaction mixture was warmed to 20° C. and stirred for 1 hour. The layerswere separated and carbon DARCO®G-60 (Activated Carbon)(57.57 g) wasadded to the organic phase. After 2 hours, the reaction mixture wasfiltered through celite 545. At this point, any remaining aqueous layerwas removed and the reaction mixture was cooled to 21° C. Next, sodiumbisulfite (20% w/w solution in water, 4330 g) was added whilemaintaining the reaction temperature below 28° C. The reaction mixturewas stirred for 17 hours and 30 minutes followed by layer separation.The organic layer was washed with water (3792 g). After another layerseparation, the organic layer containing the title compound was ready tobe use in the next stage.

HPLC: Rt=2.94 min (HPLC instrument Agilent 1100 Series analysisperformed on a Agilent Zorbax SB C18 (50×3.0 mm, 1.8 um), mobile phase:water:acetonitrile:TFA (0.05%), gradient from 0 to 95% in 2.5 min, holdfor 0.2 min, then re-equilibrate; T=60° C.; flow=1.5 mL/min)

Example 1(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E1)

Step A

To a stirred solution of(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(80 mg, P6) in dry DCM (5 mL) under argon atmosphere, at 0° C., asolution of CF₃COOH (1.5 mL) in dry DCM (5 mL) was added dropwise andthe mixture was stirred at 0° C. for 1.5 h. The solvent was evaporatedunder reduced pressure, the residue kept under vacuum for 2 hours andthen purified by preparative HPLC obtaining the trifluoroacetate salt ofthe title compound (40 mg) [System MDAP FractionLynx—Mass DirectedAutopurification System™; Target product: m/z 286 [M+H]+ (Column: LunaC18, 250×21 mm, 10 mm; Mobile phase: A: H2O+0.1% TFA; B: CH₃CN+0.1% TFA;Gradient: from 20% (B) to 35% (B) in 30 min, −>100% in 3 min, then 100%(B) for 2 min; Flow rate 17 ml/min; UV wavelength range 210-350 nm; Massrange 100-900 amu (ES+); Ionization ES+)]

Step B

To a stirred solution of this material (18 mg) in dry diethyl ether (10mL) under Argon atmosphere, at 0° C., aqueous NaOH (1M, 10 mL) was addeddropwise and the mixture was vigorously stirred for 10 minutes at roomtemperature. The phases were separated and the watery one was extractedwith diethyl ether (2×10 mL), the combined organic phases were dried onanhydrous Na₂SO₄ and the solvent removed under reduced pressureobtaining the free base of the title compound (13 mg). To a stirredsolution of this compound (13 mg) in dry diethyl ether (1.5 mL) underArgon atmosphere, at 0° C., HCl (1M in diethyl ether, 100 μL) was addeddropwise, the mixture was stirred at 0° C. for 10 minutes and for 30minutes at room temperature. The solvent was removed by decantation andthe precipitate was dried under high vacuum for 30 minutes and then forfurther two hours to give the title compound as a white solid (15 mg).

NMR (¹H, DMSO-d6): δ 8.71 (br. s., 2H) 7.73 (d, 1H) 7.59 (d, 1H) 7.41(dd, 1H) 3.45 (d, 1H) 3.09-3.16 (m, 2H) 3.04 (s, 3H) 2.92 (d, 1H)2.73-2.82 (m, 1H) 2.66 (d, 1H) 2.01-2.17 (m, 2H) 1.22-1.29 (m, 2H); MS(m/z): 286 [MH]+

Example 2a and 3a(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a) and((1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E3a)

18 mg of the free base of(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E1) were submitted to semi-preparative HPLC (chiralcolumn Chiralpak AS-H, 250×21 mm, eluent A: n-hexane; B:isopropanol+0.1% isopropyl amine, gradient isocratic 5% B, flow rate 14ml/min, detection UV at 230 nm. Retention times given were obtainedusing an analytical HPLC using a chiral column Chiralpak AS-H, 250×4.6mm, eluent A: n-hexane; B: isopropanol+0.1% isopropyl amine, gradientisocratic 5% B, flow rate 1 ml/min, detection UV at 210-340 nm.)obtaining:

Example 2a (Enantiomer 1, Rt.=7.99 min) and Example 3a (Enantiomer 2,Rt.=14.92 min).

Determination of the Absolute Configuration of 2a and 3a:

Another batch of E2a and E3a was submitted for Ab Initio VCD(vibrational circular dichroism) analysis to determine the absoluteconfiguration of these optical isomers. Example 2a (Enantiomer 1)corresponded to(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane

NMR (¹H, CDCl₃) δ ppm 7.43 (d, 1H), 7.36 (d, 1H), 7.18 (d, 1H), 3.31 (d,1H), 3.12-3.15 (m, 3H), 3.08 (d, 1H), 2.95 (d, 1H), 2.83 (d, 1H),2.73-2.80 (m, 1H), 2.63-2.70 (m, 1H), 1.91-2.00 (m, 1H), 1.79-1.87 (m,1H), 0.99-1.04 (m, 2H)

Example 3a (Enantiomer 2) corresponded to(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane

NMR (¹H, CDCl₃) δ ppm 7.43 (d, 1H), 7.35 (d, 1H), 7.17 (dd, 1H), 3.31(d, 1H), 3.13 (s, 3H), 3.08 (d, 1H), 2.95 (d, 1H), 2.83 (d, 1H),2.72-2.80 (m, 1H), 2.62-2.70 (m, 1H), 1.89-2.00 (m, 1H), 1.77-1.87 (m,1H), 0.94-1.07 (m, 2H)

Example 2a(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a)

Method B:

1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P60, 10 grams, 25.8 mmol) was dissolved in toluene (100 mL). Thesolution was treated with triethylsilane (3.6 grams, 4.96 mL, 31.1 mmol,1.2 eq) followed by trifluoroacetic acid (20 grams, 13.46 mL, 181.2mmol, 7 eq). The reaction was stirred at room temperature for 48 hrs,then quenched with 1N sodium hydroxide (100 mL) and stirred for 10 min.The pH of the mixture was approximately 13. The phases were separatedand the toluene phase was washed with 1N sodium hydroxide (100 mL) andwater (10 mL) then concentrated in vacuo to give the product as an oil(8.5 grams).

NMR (¹H, CDCl₃): δ ppm 0.98-1.04 (m, 2H) 1.75-1.87 (m, 2H) 1.89-1.99 (m,1H) 2.59-2.70 (m, 1H) 2.71-2.80 (m, 1H) 2.82 (d, J=9.80 Hz, 1H) 2.94 (d,J=9.89 Hz, 1H) 3.07 (d, J=12.91 Hz, 1H) 3.12 (d, J=1.01 Hz, 3H) 3.31 (d,J=12.82 Hz, 1H) 7.11-7.21 (m, 1H) 7.35 (dd, J=8.29, 0.96 Hz, 1H) 7.43(d, J=2.11 Hz, 1H)

Method C:

(2R,3R)-2,3-bis[(phenylcarbonyl)oxy]butanedioicacid-(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(1:1) (E34, 37.8 g, 58.7 mmol,) were diluted in DCM (500 ml) and treatedwith aqueous K₂CO₃ 10% w/w (500 ml). Phases were separated and theaqueous layer was back-extracted with DCM (1×400 mL). The collectedorganic phases, dried (Na₂SO₄), were evaporated to give title compound(17.4 g).

NMR (¹H, CDCl₃): δ ppm 7.45 (s, 1H), 7.36 (d, 1H), 7.19 (d, 1H), 3.32(d, 1H), 3.14 (s, 3H), 3.09 (d, 1H), 2.96 (d, 1H), 2.84 (d, 1H),2.73-2.81 (m, 1H), 2.64-2.71 (m, 1H), 1.92-2.00 (m, 1H), 1.79-1.88 (m,1H), 0.97-1.07 (m, 2H).

Chiral HPLC: (Column: AS-H (25×0.46 cm); Eluent:n-Hexane/(2-propanol+0.1% isopropylamine) 95/5 v/v; Flow: 1 ml/min; DAD:210-340 nm; CD: 230 nm; Enant1 (Rt=7.828 min)/Enant2 (Rt=14,430min)==98.88/1.12 area

Optical rotation analysis was performed on a further batch of E2a;optical rotation was measured at 589 nm (sodium ‘D’ line) using aRudolph Research Analytical AUTOPOL V polarimeter. Experimentalconditions: Cell: 0.5 dm (50 mm) thermostated micro-cell held at 25° C.;solvent: CCl₄; conc.: 38 mg/450 μl=8.4 gm/1200 ml. Observed Rotation:α=−0.23°; Specific rotaion [α]_(D)=−5.47.

Example 2b(1S,6R)-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E2b)

Method A:

To a solution of(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a, amount obtained from the chiral semi-preparative HPLC describedabove) in DCM (0.2 ml) was added 1 equivalent of HCl (1M in Et₂O), thesolvent evaporated under vacuo and the material thus obtained trituratedwith Et₂O to give 5 mg of the title compound as a white slightlyhygroscopic solid.

Method B:

(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.]heptane(E2a, 4.6 g, 16.07 mmol) was dissolved in Et₂O (60 ml) and the solutioncooled to 0° C. (ice bath). Hydrochloric acid 1M in diethyl ether (17.68ml, 1.1eq.) was dropwise added at 0° C. under stirring. A whitesuspension was formed and the mixture was stirred at 25° C. for 2 hrs.The solid was filtered, washed with diethyl ether (46 ml) and driedunder vacuum at 40° C. for 12 hrs to give the title compound (5.0 g) aswhite solid. 96% yield.

NMR (¹H, DMSO-d6, 600 MHz): δ(ppm): 9.05 (bs, 2H), 7.77 (d, 1H), 7.59(d, 1H), 7.45 (dd, 1H), 3.46 (d, 1H), 3.14 (m, 1H), 3.13 (d, 1H), 3.06(s, 3H), 2.99 (d, 1H), 2.79 (m, 1H), 2.63 (d, 1H), 2.17 (m, 1H), 2.07(m, 1H), 1.30 (d, 1H), 1.27 (d, 1H)

Example 3b(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E3b)

To a solution of((1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E3a, amount obtained from the chiral semi-preparative HPLC describedabove) in DCM (0.2 ml) was added 1 equivalent of HCl (1M in Et₂O), thesolvent evaporated under vacuo and the material thus obtained trituratedwith Et₂O to give 5 mg of the title compound as a white slightlyhygroscopic solid

Example 4[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E4)

Method A:

2,6-Bis(1,1-dimethylethyl)-4-methylpyridine (35.836 g) was added underArgon atmosphere to a solution of CH₂I₂ (46.9 g) in dry DCM (260 mL),then ZnEt₂ (1M in hexane, 87.5 mL) was added dropwise at 0° C. over 5mins. After stirring at 0° C. for 30 minutes, the reaction mixture wascooled at −20° C., a solution of 1,1-dimethylethyl4-(3,4-dichlorophenyl)-5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(2 g, P4) in dry DCM (20 mL) was added dropwise and the reaction mixturewas stirred at −20° C. for additional 30 mins and then overnight at roomtemperature. Aqueous HCl (1M, 300 mL) was added and the reaction mixturewas vigorously stirred for 20 minutes, the phases were separated and thewatery layer was basified to pH=12 with NaOH 3M. The watery solution wasextracted with diethyl ether (3×150 mL), the organic phase wasevaporated and the residue was taken up with saturated NH₄Cl (100 mL)and diethyl ether (100 mL) and the mixture was vigorously stirred for 10mins, then the phases were separated. The watery phase was washed withdiethyl ether (3×50 mL), then was basified to pH=12 with NaOH 3M andextracted with diethyl ether (3×150 ml).

The combined organic phases were dried on anhydrous Na₂SO₄ and thesolvent was removed under reduced pressure to give 840 mg of impurematerial.

MS (m/z): 272 [MH]⁺.

Method B:

To a stirred solution of methyl6-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate(P16, 0.5 g) in THF (2.5 mL), at 0° C. and under a nitrogen atmosphere,BH₃THF complex (1M/THF, 12.8 mL) was added dropwise, then the reactionmixture was allowed to reach RT and stirred at reflux for 5 h. 1 mL ofMeOH and 5 mL of HCl 1.0M in Et₂O were added to the reaction mixture andthe solution was stirred at room temperature for 2 hours. The mixturewas concentrated under reduced pressure and the crude product waspurified by FC (eluting with DCM/methanol/aqueous 28% NH₄OH 9/1/0.1) togive 82 mg of the title compound as a yellow oil.

Method C:

(1S,6R/1R,6S)-1,1-dimethylethyl-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P5, 50 mg, impure compound obtained as described in P5, Method A) waspurified by preparative HPLC (Column:Luna C18, 250×21 mm, 10 mm; mobilephase: A: H2O+0.1% TFA; B: CH₃CN+0.1% TFA; gradient: from 15% (B) to 35%(B) in 30 min, −>100% in 3 min, then 100% (B) for 2 min; flow rate: 17ml/min; UV wavelength range: 210-350 nm) obtaining its trifluoroacetatesalt (23 mg).

To a stirred solution of this product (23 mg) in dry diethyl ether (10mL) under argon atmosphere, at 0° C., NaOH (1M, 10 mL) was addeddropwise and the mixture was vigorously stirred for 10 minutes at roomtemperature then the phases were separated and the watery one wasextracted with diethyl ether (2×10 mL). The combined organic phases weredried on anhydrous Na₂SO₄ and the solvent was removed at reducedpressure obtaining the free base of the title compound (16 mg).

Example 5a and 6a [(1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E5a) and [(1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E6a)

[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E4, 82 mg) was submitted to semi-preparative HPLC (chiral columnChiralpak AD-H, 25×4.6 cm, eluent A: n-hexane; B: isopropanol+0.1%isopropylamine 70/30 v/v, flow rate 0.8 ml/min., detection UV at 230nm.) obtaining:

[(1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E5a, Enantiomer 1, Rt.=6.263 min) and [(1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E6a, Enantiomer 2, Rt.=15.699 min).

Example 5b [(1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanolhydrochloride (E5b)

To a solution of [(1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E5a, amount obtained from the preparation described above) in DCM wasadded 1 equivalent of HCl (1M in Et₂O), the solvent evaporated in vacuoand the material thus obtained triturated with Et₂O to give 30 mg of thecorresponding hydrochloride salt as a white slightly hygroscopic solid.

Example 6b [(1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E6b)

To a solution of [(1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E6a, amount obtained from the preparation described above) in DCM wasadded 1 equivalent of HCl (1M in Et₂O), the solvent evaporated in vacuoand the material thus obtained triturated with Et₂O to give 30 mg of thecorresponding hydrochloride salt as a white slightly hygroscopic solid.

NMR (¹H, DMSO-d6): d ppm 8.78 (d, 2H) 7.76 (d, 1H) 7.58 (dd, 1H)7.37-7.46 (m, 1H) 4.75 (t, 1H) 3.49-3.60 (m, 1H) 3.06-3.23 (m, 2H)2.95-3.05 (m, 1H) 2.72-2.88 (m, 2H) 1.99-2.21 (m, 2H) 1.15-1.26 (m, 2H)

Example 7(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]-methanolhydrochloride (E7)

To a stirred solution of[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol(E4, 16 mg) in dry diethyl ether (1.5 mL) under argon atmosphere, at 0°C., HCl (1M in diethyl ether, 0.12 ml) was added dropwise, the mixturewas stirred at 0° C. for 10 minutes and for 30 minutes at roomtemperature. The solvent was removed by decantation and the precipitatewas dried under high vacuum for 30 minutes to give the titled compoundas white solid (18 mg).

NMR (¹H, DMSO-d6): δ 8.66 (br. s., 2H) 7.73 (d, 1H) 7.57 (d, 1H) 7.40(dd, 1H) 4.75 (t, 1H) 3.52 (d, 1H) 3.06-3.18 (m, 2H) 2.93-3.03 (m, 1H)2.70-2.83 (m, 2H) 1.99-2.17 (m, 2H) 1.15-1.24 (m, 2H); MS (m/z): 272[MH]⁺

Examples 8(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E8)

To a solution of(1R,6R/1S,6S)-1-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one and(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptan-4-one(640 mg, P11) in dry tetrahydrofurane (16 ml) borane THF (1M in THF,7.53 ml) was added under N₂ and the mixture heated at reflux for 3 h andat room temperature over night and then heated at reflux for 2 h. Themixture was then cooled to 0° C. and methanol (8 mL) followed byhydrochloric acid (1M/ether, 25 mL) were cautiously added monitoring gasevolution and the solution stirred at room temperature over night.Solvents were then removed in vacuo and potassium carbonate (10%solution) was added to the residue. The aqueous layer was extracted withdichloromethane, then the organic phase was washed with a NaCl saturatedsolution, dried and concentrated under reduced pressure. The titlecompound was separated by aminic cartridge (eluting withcyclohexanemethyl acetate from 9/1 to 7/3) to give the title compound in150 mg yield.

NMR (¹H, CDCl₃): δ 7.37 (m, 2H), 7.15 (d, 1H), 3.35 (m, 1H), 3.12 (d,1H), 2.78 (m, 2H), 2.05 (m, 2H), 1.35 (m, 1H), 1.04 (m, 1H), 0.94 (m,1H); MS (m/z): 242 [MH]⁺.

Example 9a and 10a(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E9a) and(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E10a)

(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E8, 150mg) was submitted to semi-preparative HPLC (chiral column ChiralpakAD-H, 25×4.6 cm, eluent A: n-hexane; B: isopropanol+0.1% isopropylamine99/1 v/v, flow rate 1 ml/min. detection UV at 230 nm.) obtaining:

Example 9a (E9a, Enantiomer 1, Rt.=15.22 min) and Example 10a (E10a,Enantiomer 2, Rt.=15.33 min).

Determination of the absolute configuration of 9a and 10a: A new batchof E9a (7 mg) and E10a (9 mg)(prepared following an analogous procedureto that described below for 9B and 10B and then treating thecorresponding hydrochloride salts with NaOH to obtain the free bases)was submitted to Ab Initio VCD (vibrational circular dichroism) andcomparative VCD analysis to determine the absolute configuration ofthese optical isomers.

Example 9a (enantiomer 1) corresponded to(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane

NMR (¹H, CDCl₃): δ ppm 7.32-7.37 (m, 2H), 7.10 (dd, 1H), 3.34 (dd, 1H),3.07 (d, 1H), 2.51-2.79 (m, 2H), 1.97-2.08 (m, 1H), 1.85-1.97 (m, 1H),1.21-1.36 (m, 1H), 0.92-1.01 (m, 1H), 0.81-0.91 (m, 1H)

Example 10a (enantiomer 2) corresponded to(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane:

NMR (¹H, CDCl₃): δ ppm 7.32-7.37 (m, 2H), 7.10 (dd, 1H), 3.34 (dd, 1H),3.07 (d, 1H), 2.51-2.79 (m, 2H), 1.97-2.08 (m, 1H), 1.85-1.97 (m, 1H),1.21-1.36 (m, 1H), 0.92-1.01 (m, 1H), 0.81-0.91 (m, 1H)

Example 9b (1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptanehydrochloride (E9b)

To a solution of(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E9a, 40 mg)in DCM was added 1 equivalent of HCl (1M in Et₂O), the solventevaporated in vacuo and the material thus obtained triturated with Et₂Oto give 45 mg of the title compound as a white slightly hygroscopicsolid.

NMR (¹H, MeOH-d₄): δ ppm 7.52 (d, 1H) 7.45 (d, 1H) 7.28 (dd, 1.52 Hz,1H) 3.46-3.65 (m, 7.07 Hz, 1H) 3.10 (d, 1H) 2.88-3.04 (m, 1H) 2.49-2.82(m, 1H) 1.97-2.28 (m, 2H) 1.37-1.56 (m, 1H) 1.07-1.19 (m, 1H) 0.92-1.06(m, 1H)

Example 10b (1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptanehydrochloride (E10b)

To a solution of(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane (E10a, 40 mg)in DCM was added 1 equivalent of HCl (1M in Et₂O), the solventevaporated in vacuo and the material thus obtained triturated with Et₂Oto give 45 mg of the title compound as a white slightly hygroscopicsolid.

NMR (¹H, MeOH-d₄): δ ppm 7.52 (d, 1H) 7.45 (d, 1H) 7.28 (dd, 1.52 Hz,1H) 3.46-3.65 (m, 7.07 Hz, 1H) 3.10 (d, 1H) 2.88-3.04 (m, 1H) 2.49-2.82(m, 1H) 1.97-2.28 (m, 2H) 1.37-1.56 (m, 1H) 1.07-1.19 (m, 1H) 0.92-1.06(m, 1H)

Example 11(1S,4R,6R/1R,4S,6S)-6-(3,4-dichlorophenyl)-4-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E11)

1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-(hydroxymethyl)-4-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate(P68, 70 mg) was dissolved in DMF (30 mL) and cooled to 0° C.; thensodium hydride 60% dispersed on mineral oil (10.9 mg) was addedportionwise. The mixture was stirred at 0° C. for 30 min and theniodomethane (0.017 mL) was added. The mixture was slowly warmed to roomtemperature and stirred for 1.5 h. Further 7.2 mg of sodium hydride 60%dispersed on mineral oil and 0.017 mL of iodomethane were added and themixture was stirred for an additional hour. The reaction mixture wasthen quenched with a saturated solution of NH₄Cl (30 mL) and Et₂O (30mL) added. The aqueous phase was washed with Et₂O (3×30 mL), the organicphases combined, dried over Na₂SO₄ and concentrated. Purification bychromatography on silica gel eluting with a gradient 10%-30% ethylacetate/cyclohexane afforded a compound (50 mg) that was dissolved inDCM (1.2 mL), cooled to 0° C. and reacted with trifluoroacetic acid(0.22 mL). The mixture was slowly warmed to room temperature and stirredat this temperature for 2 h. The volatiles were evaporated under vacuumand the residue purified by SCX cartridge eluting first with MeOH andthen with 2.0M NH₃ in MeOH. Further purification by preparative HPLCafforded the title compound, 20 mg.

XBridge PREP C18, 100×19 mm, 5 μm

Mobile phase:H₂O+0.1% TFA; B: CH₃CN

Gradient:20(B) for 1 min, 20% to 35% (B) in 12 min, 35% to 100% (B) in0.5 min, 100% (B) for 1.5 min

Flow rate:17 mL/min

NMR (¹H, CDCl₃): δ 7.46 (d, 1H), 7.33 (d, 1H), 7.20 (dd, 1H), 3.54 (d,1H), 3.06-3.17 (m, 3H), 2.89-3.01 (m, 2H), 2.72 (d, 1H), 2.27-2.53 (m,1H), 1.91-2.07 (m, 1H), 1.27-1.46 (m, 1H), 1.04 (d, 3H), 0.87-0.98 (m,2H). MS (m/z): 300 [M+H]⁺.

Example 12(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E12)

(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a, 25 mg) was dissolved in methanol (1 mL); acetic acid (0.015 mL)was added followed by sodium triacetoxyborohydride (27.8 mg) andformaldehyde 37% in water (0.06 mL). The reaction mixture was stirred atroom temperature overnight. Volatiles were then evaporated and theresidue partitioned between DCM (20 mL) and aqueous sat NaHCO₃ (20 mL)solution, dried and concentrated. Purification by chromatography (NHcolumn) eluting with a gradient 0-100% ethyl acetate-cyclohexaneafforded the title compound (16 mg).

NMR (¹H, CDCl₃): δ 7.44 (d, 1H), 7.35 (d, 1H), 7.18 (dd, 1H), 3.15 (s,3H), 2.90 (dd, 2H), 2.78 (d, 1H), 2.70 (d, 1H), 2.23-2.30 (m, 5H),1.96-2.13 (m, 2H), 1.05 (d, 1H), 1.01 (d, 1H); MS (m/z): 300 [M+H]⁺.

Example 13(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E13)

(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E12, 16 mg) was treated with hydrochloric acid 1.0M in diethyl ether(0.064 mL). 0.5 mL of diethyl ether were added and a colourless solidformed. Organic phase was removed after decantation of the solid.Colouness solid obtained as a 5:1 mixture of isomers due protonation onthe nitrogen atom (16 mg).

NMR (¹H, DMSO-d6): δ 10.49 (br. s., 1H), 7.84 (d, 1H), 7.57-7.65 (m,1H), 7.51-7.55 (m, 1H), 3.68-3.66 (m, 1H), 3.22-3.35 (m, 1H), 3.00-3.17(m, 5H), 2.76-2.93 (m, 2H), 2.68-2.75 (m, 3H), 2.29-2.43 (m, 1H),2.10-2.21 (m, 1H), 1.32 (d, 1H), 1.27 (d 1H) (peaks referred to the mainspecies); MS (m/z): 300 [MH]⁺.

Example 14(1R,6S/1S,6R)-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E14)

Step A

1,1-dimethylethyl(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P27, 0.3 g) was dissolved in DMF (5 mL) and cooled to 0° C.; NaH 60% inmineral oil (39 mg) was added and the reaction mixture was stirred at 0°C. for 30 minutes. Iodomethane (92 μl) was then added and mixture slowlywarmed to room temperature. Further 2 addition of NaH (20 mg) and MeI(50 μl) each were done and the mixture stirred for an overall time of1.5 hours. The reaction mixture was then quenched at 0° C. with asaturated solution of NH₄Cl (5 mL) and diluted with diethyl ether (20mL); the organic phase was separated, washed with brine (20 mL), driedand concentrated under vacuum. The crude mixture was then purified bychromatography on silica gel eluting with a gradient 10-50%ethylacetate/cyclohexane to afford 1,1-dimethylethyl(1R,6S)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylateas colourless oil (107 mg).

MS (m/z): 420 [MH]⁺, 363 [M-56]⁺.

Step B

1,1-dimethylethyl(1R,6S)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylatecoming from step A was dissolved in DCM (4 mL) and TFA (0.2 mL) wasadded to the solution. The reaction mixture was stirred at roomtemperature for 1 hour and then volatiles were evaporated in vacuo. Theresidue was dissolved in DCM (10 mL), washed with a saturated solutionof NaHCO₃ (10 mL), brine (10 mL), dried and concentrated under vacuum.The residue was purified initially on a SCX cartridge eluting first withMeOH followed by 2.0N NH₃ in MeOH and then by chromatography on silicagel eluting with a gradient 3% MeOH/DCM to 8% MeOH/DCM+2% 2.0N NH₃ inMeOH to give 55 mg of the title compound.

NMR (¹H, CDCl₃): δ 7.72 (d, 1H), 7.48-7.53 (m, 1H), 7.42-7.46 (m, 1H),3.42 (d, 1H), 3.08-3.14 (m, 4H), 3.04 (d, 1H), 2.81-2.90 (m, 1H),2.66-2.76 (m, 2H), 1.97-2.06 (m, 1H), 1.85-1.93 (m, 2H), 1.11 (d, 1H),1.04 (d, 1H);); MS (m/z): 320 [MH]⁺.

Example 15(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E15)

To a solution of(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E14, 55 mg) in DCM was added 1 equivalent of HCl (1M in Et₂O), thesolvent evaporated in vacuo and the material thus obtained trituratedwith Et₂O to give 61 mg of the title compound as a white solid.

NMR (¹H, DMSO-d6): δ 8.48-8.86 (m, 2H), 7.95 (s, 1H), 7.63-7.77 (m, 2H),3.51 (d, 1H), 3.13-3.22 (m, 2H), 3.03 (s, 3H), 2.73-2.88 (m, 2H),2.72-2.88 (m, 2H), 2.05-2.16 (m, 1H), 1.26-1.36 (m, 2H)); MS (m/z): 320[MH]⁺.

Example 16(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E16).

To an ice cooled solution of 1,1-dimethylethyl(1R,6S/1S/6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P32, impure compound obtained with a similar procedure to thatpreviously described for P32, 280 mg) in dichloromethane (5 mL) undernitrogen, trifluoroacetic acid (1 mL) was added dropwise. The reactionmixture was allowed to room temperature and then stirred for 1 h. Thesolvent was evaporated under reduced pressure. The crude material waspurified through a SCX (5 g) column, then was submitted to preparativeHPLC (column: Luna AXIA C18, 100×21 mm, 5 um; Mobile phase: A: H2O+0.1%TFA; B: CH₃CN; Gradient: 15% (B) δ 35% (B) in 15 min (curve 7*), 35%(B)→100% (B) in 2 min, 100% (B) for 0.1 min; Flow rate 17 ml/min; UVrange: 210-350 nm; Mass range: 100-900 amu (ES+); Ionization: ES+). Thecompound obtained was passed through a SCX column to afford the titlecompound (70 mg).

NMR (¹H, CDCl₃): δ ppm 7.25 (s, 4H) 3.30 (d, 1H) 3.08-3.14 (m, 4H)2.85-2.91 (m, 2H) 2.63-2.80 (m, 2H) 1.81-1.99 (m, 2H) 0.99-1.05 (m, 2H).

Example 17(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E17)

To a solution of(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E16, 70 mg) in anhydrous dichloromethane (2 mL) was added HCl 1.0M inanhydrous diethylether (0.278 mL). The solvent was evaporated underreduced pressure and the resulting solid was triturated with anhydrousdiethylether to give the title compound (76 mg).

NMR (¹H, DMSO-d₆): δ ppm 8.33-9.07 (m, 2H) 7.44 (d, 2H) 7.38 (d, 2H)3.47 (d, 1H) 3.15 (d, 1H) 3.07-3.19 (m, 1H) 3.00-3.07 (m, 3H) 2.94 (d,1H) 2.74-2.84 (m, 1H) 2.58 (d, 1H) 2.09-2.23 (m, 1H) 1.96-2.09 (m, 1H)1.27 (d, 1H) 1.21 (d, 1H)

Example 18(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E18)

Step A

To a stirred solution of 1,1-dimethylethyl(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P51, 78 mg) in dry DCM (5 mL), under a nitrogen atmosphere,trifluoroacetic acid (1.5 mL) was added and the stirring continued for 2hrs. After this period of time toluene was added and the solventevaporated obtaining a crude product that was dissolved in DCM, theorganic phase was washed with aqueous concentrated NaHCO₃ solution, theorganic solvent evaporated. The crude product was purified first byflash-chromatography (eluting with DCM/(Methanol+1% 2N NH₃ in MeOH) from0 to 20%) and then by LC-MS to give 27 mg of(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane,the free base of the title compound.

Step B

10 mg of this compound were dissolved in DCM (1 ml) and 1 equivalent of1N HCl in Et₂O was added. The solvent was removed in vacuo to give titlecompound (12 mg).

NMR (¹H, MeOH-d₄): δ 7.58 (d, 1H) 7.38 (d, 1H) 7.25 (dd, 1H) 3.64 (d,1H) 3.15 (m, 5H) 2.79 (m, 1H) 2.57 (d, 1H) 2.11 (m, 2H) 1.19 (d, 1H)1.12 (d, 1H) 0.98 (t, 3H);

MS (m/z): 300 [MH]+

Example 19a and 20a (1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E19a) and (1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E20a)

(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E18, 28 mg) was then submitted to semi-preparative SFC togive the separated enantiomers, by using a chiral column Chiralpak AD-H(25×4.6 cm), eluent 2-propanol+0.1% isopropylamine 13%, T 35° C., P 100bar, flow rate 2.0 mL/min, detection DAD 210-340 nm, CD 225 nm.obtaining:

Example 19a (Enantiomer 1, Rt.=14.36 min, 11 mg, colourless oil, MS(m/z): 300 [MH]⁺) and Example 20a (enantiomer 2, Rt.=15.70 min, 7 mg,colourless oil, MS (m/z): 300 [MH]+).

Example 19b (1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E19b)

To a solution of (1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E19a, 11 mg) in DCM (0.2 ml) was added 1 equivalent of HCl (1M inEt₂O), the solvent evaporated under vacuo and the material thus obtainedtriturated with Et₂O to give 8.9 mg of the title compound as a whiteslightly hygroscopic solid.

MS (m/z): 300 [MH]⁺

Example 20b (1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E20b)

To a solution of (1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E20a, 7 mg) in DCM (0.2 ml) was added 1 equivalent of HCl (1M in Et₂O),the solvent evaporated under vacuo and the material thus obtainedtriturated with Et₂O to give 5.8 mg of the title compound as a whiteslightly hygroscopic solid.

NMR (¹H, MeOH-d₄): δ 7.70 (d, 1H) 7.49 (d, 1H) 7.36 (dd, 1H) 3.75 (d,1H) 3.37 (m, 1H) 3.26 (m, 3H) 3.15 (m, 1H) 2.89 (m, 1H) 2.69 (d, 1H)2.23 (q, 2H) 1.29 (d, 1H) 1.23 (d, 1H) 1.13 (t, 3H); MS (m/z): 300 [MH]⁺

Example 21(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptane(E21)

To a stirred solution of(1S,6R/1R,6S)-1,1-dimethylethyl-1-(hydroxymethyl)-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate(P36,173 mg) in dry THF (3 mL) under N₂ atmosphere, at 0° C., NaH (60%on mineral oil, 24 mg) was added and the stirring continued for 30minutes. CH₃I (52 μL) was added dropwise and the reaction was slowlywarmed to room temperature and stirred for 3 h. Saturated NH₄Cl aqueoussolution was added and then the mixture was concentrated in vacuo. Theaqueous phase was extracted with diethyl ether (2 times) and then thecombined organic layers were washed with saturated NaCl aqueoussolution, dried on anhydrous Na₂SO₄, and evaporated obtaining a crudeproduct. The crude was dissolved in dry DCM (4 mL) and TFA (3.5 mL) wasadded under N₂ atmosphere at 0° C. The reaction was slowly warmed toroom temperature and stirred for 1 h. The mixture was concentrated invacuo and the residue was purified by a SCX cartridge. The crude thusobtained was purified by HPLC chromatography to give the title compound(35 mg).

Conditions LC: Column Luna AXIA C18, 100×21 mm, 5 μm

Mobile phase A: H2O+0.1% TFA; B: CH₃CN

Gradient: from 20% (B) to 35% (B) in 18 min, from 35% (B) to 80% (B) in7 min, from 75% (B) to 100% (B) in 1 min, 100% (B) for 3 min.

Flow rate 17 ml/min

UV range 210-350 nm

Mass range 100-900 amu (ES+)

Ionization ES+

R_(t)=3.37 min

MS (m/z): 302[M+H]⁺

Example 22(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptanehydrochloride (E22)

To a stirred solution of(1S,6R/1R,6S)-1-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptane(E21, 35 mg) in dry diethyl ether HCl (1M in diethyl ether, 0.12 ml) wasadded dropwise. The solvent was removed by decantation and theprecipitate was dried under vacuum to give the title compound as whitesolid (30 mg).

NMR (¹H, MeOH-d₄): δ ppm 7.52 (d, 2H) 7.24 (d, 2H) 3.72 (d, 1H) 3.27 (d,1H) 3.25-3.21 (m, 1H) 3.16-3.12 (m, 3H) 3.07 (d, 1H) 2.97-2.84 (m, 1H)2.74 (d, 1H) 2.32-2.12 (m, 2H) 1.31 (d, 1H) 1.22 (d, 1H)

Example 23(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E23)

Step A

To a stirred solution of (1S,6R/1R,6S)-phenylmethyl6-[3-chloro-4-(trifluoromethyl)phenyl]-1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(430 mg) (P41, impure compound coming from preparation above described)in dry THF (6 mL) under N₂ atmosphere, at 0° C., NaH (60% on mineraloil, 59 mg) was added and the stirring was continued for 30 minutes.CH₃I (113 μL) was added dropwise and the reaction was allowed to reachroom temperature and stirred overnight. Saturated NH₄Cl aqueous solutionwas added and then the mixture was concentrated in vacuo. The aqueousphase was extracted with diethyl ether (2 times) and then the combinedorganic layers were washed with saturated NaCl aqueous solution, driedon anhydrous Na₂SO₄, and evaporated obtaining a crude product. The crudewas purified by flash-chromatography (eluting with cyclohexane/ethylacetate from 9:1 to 8:2) to give 300 mg of impure phenylmethyl(1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate.

Step B

The impure product thus obtained was dissolved in dry 1,4-dioxane (6 mL)and to the solution a HCl 6N (1 mL) solution was added. The reactionmixture was refluxed for 4 h and then further HCl 6 N (2 mL) was addedto the solution. It was stirred at RT overnight and then refluxed for 5h. The reaction was quenched with aqueous NaOH 3N (pH=12) solution andextracted with Et₂O (3 times). The combined organic layers were washedwith saturated NaCl aqueous solution, dried and concentrated in vacuo.The residue was purified by a SCX cartridge. The crude thus obtained waspurified by HPLC chromatography to give the free base of the titlecompound (20 mg).

Conditions LC chromatography: Column Gemini C18 AXIA, 50×21 mm, 5 μm

Mobile phase A: NH₄HCO3 10 mM aq. sol, pH=10; B: CH3CN

Gradient: from 30% (B) to 35% (B) in 1 min, from 35% (B) to 75% (B) in 7min, from 75% (B) to 100% (B) in 1 min, 100% (B) for 1 min.

Flow rate 17 ml/min UV range 210-350 nm

Mass range 100-900 amu (ES+)

Ionization ES+

R_(t)=3.38 min

MS (m/z): 320[M+H]+

Example 24(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanehydrochloride (E24)

To a stirred solution of the(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E23, 20 mg) in dry diethyl ether HCl (1M in diethyl ether) was addeddropwise. The solvent was removed by decantation and the precipitate wasdried under vacuum to give the titled compound as white solid (21 mg).

NMR (free base, ¹H, CDCl₃): δ ppm 7.71 (s, 1H) 7.46 (dd, 2H) 3.40 (d,1H) 3.12 (s, 3H) 2.99-3.10 (m, 2H) 2.76-2.91 (m, 1H) 2.65-2.76 (m, 2H)1.91-2.07 (m, 2H) 1.79-1.91 (m, 1H) 1.10 (d, 1H) 1.02 (d, 1H); MS (m/z):320 [MH]⁺

Example 25(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E25)

Phenylmethyl(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate(P44, 600 mg) was dissolved in 1,4-dioxane (7 mL) and aqueous 6.0N HCl(7 mL) was added. The reaction mixture was refluxed for 4 hours and thenheated to 85° C. for 18 hours. After cooling to room temperature, theaqueous phase was washed with diethyl ether (30 mL), basified with 3.0MNaOH and extracted with DCM (3×50 mL). Organics were combined, driedover Na₂SO₄ and concentrated. The crude reaction was purified bychromatography on silica gel eluting with 5% MeOH/DCM at first and thenwith 5% MeOH/DCM+2% 2.0M NH₃ in MeOH. The title compound was obtained ascolourless oil (145 mg).

NMR (¹H, CDCl₃): δ 7.77-7.86 (m, 3H), 7.72-7.76 (m, 1H), 7.42-7.52 (m,3H), 3.37 (d, 1H), 3.18 (d, 1H), 3.10 (s, 3H), 3.02 (d, 1H), 2.80-2.89(m, 2H), 2.70-2.79 (m, 1H), 1.96-2.08 (m, 2H), 1.25 (d, 1H), 1.11 (d,1H);); MS (m/z): 268 [MH]⁺.

Example 26a and 27a (1R,6S or1S,6R)-1-[(methyloxy)methyl]-6(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E26a) and (1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E27a)

(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E25, 140 mg) were submitted to semi-preparative HPLC using a chiralcolumn Chiralcel OJ, 25×4.6 cm, eluent A: n-hexane; B: ethanol 0.1%isopropylamine-85/15, flow rate 0.9 mL/min, detection UV at 228 nmobtaining:

Example 26a (Enantiomer 1, Rt.=5.77 min, 52 mg, colourless oil) andExample 27a (Enantiomer 2, Rt.=7.40 min, 40 mg, colourless oil).

Example 28(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptanehydrochloride (E28)

To a solution(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E25, 5 mg) in DCM was added 1 equivalent of HCl (1M in Et₂O), thesolvent evaporated in vacuo and the material thus obtained trituratedwith Et₂O to give 5 mg of the corresponding hydrochloride salt as awhite solid.

MS (m/z): 268 [MH]⁺.

Example 26b (1R,6S or 1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3,azabicyclo[4.1.0]heptane hydrochloride (E26b)

To a solution of (1R,6S or1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E26a, 52 mg) in DCM was added 1 equivalent of HCl (1M in Et₂O), thesolvent evaporated in vacuo and the material thus obtained trituratedwith Et₂O to give 53 mg of the title compound as a white solid.

NMR (¹H, CDCl₃): δ 7.24-7.32 (m, 4H), 7.09-7.14 (m, 1H), 6.90-6.98 (m,2H), 3.32 (d, 1H), 2.76-2.88 (m, 2H), 2.60-2.65 (m, 1H), 2.54-2.58 (m,3H), 2.40-2.49 (m, 1H), 2.24-2.29 (m, 1H), 1.99-2.10 (m, 1H), 1.76-1.84(m, 1H), 0.92-0.95 (m, 1H), 0.80-0.84 (m, 1H); MS (m/z): 268 [MH]⁺.

Example 27b (1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptanehydrochloride (E27b)

To a solution of (1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane(E27a, 40 mg) in DCM was added 1 equivalent of HCl (1M in Et₂O), thesolvent evaporated in vacuo and the material thus obtained trituratedwith Et₂O to give 40 mg of the title compound as a white solid.

NMR (¹H, DMSO-d6): δ 7.83-7.90 (m, 3H), 7.80-7.83 (m, 1H), 7.60 (dd,1H), 7.44-7.52 (m, 2H), 3.20-3.40 (m, 1H), 3.13 (d, 1H), 2.93-3.05 (m,5H), 2.74-2.83 (m, 1H), 2.63 (d, 1H), 1.99-2.17 (m, 2H), 1.25-1.32 (m,2H)); MS (m/z): 268 [MH]⁺.

Example 29(1S,6R/1R,6S)-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.00]heptanehydrochloride (E29)

The title compound was prepared according to a similar procedure to thatdescribed for Example 18 in 115 mg yield starting from(1S,6R/1R,6S)-1,1-dimethylethyl6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(164 mg, P50).

NMR (¹H, DMSO-do): δ ppm 8.28 (s, 1H) 7.66 (d, 1H) 7.25-7.47 (m, 2H)3.41 (d, 1H) 3.01-3.14 (m, 5H) 2.92 (d, 1H) 2.75 (d, 1H) 2.68 (d, 1H)1.98-2.10 (m, 2H) 1.17-1.26 (m, 2H); MS (m/z): 270 [MH]⁺

Example 30 (1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1{[(2,2,2-trifluoroethyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane (E30)

Step a)

To a stirred solution of 2,2,2-trifluoroethanol (12 μl) in DMF (1 mL)sodium hydride (60% in mineral oil, 5.7 mg) was added followed, after 10min, by a solution of 1-dimethylethyl(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(methylsulfonyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate(P69, 60 mg), in DMF (2 mL). After 4 hrs, further 2,2,2-trifluoroethanol(12 μL) in DMF (1 mL) and sodium hydride (60% in mineral oil, 5.7 mg)were added. After 2 days further 2,2,2-trifluoroethanol (12 μL) in DMF(1 mL), and sodium hydride (5.7 mg) were added and the reaction washeated to 60° C. for 5 hrs. DCM and NaHCO₃ saturated solution were addedand the solvent was removed under reduced pressure to give1,1-dimethylethyl(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane-3-carboxylateas crude (6 mg).

Step b)

The crude 1,1-dimethylethyl(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane-3-carboxylate(6 mg, E30, Step a) was dissolved in dry DCM (1 mL) and TFA (0.5 mL) wasadded. The reaction mixture was stirred for 2 hrs and after this periodof time the solvent was evaporated to give a crude that was redissolvedin DCM. The organic phase was washed with NaHCO₃ saturated solution,dried and concentrated. The crude product was purified byflash-chromatography (eluting with DCM/Methanol/NH₃/MeOH 2N 49/1/1) togive the title compound (3.9 mg).

NMR (¹H, CDCl₃): δ 7.5 (s, 1H) 7.45 (d, 1H) 7.35 (m, 1H), 3.9 (d, 2H)3.7 (d, 1H) 3.6 (m, 2H) 3.25 (d, 1H) 3.15 (m, 2H) 2.3 (m, 1H) 2.2 (m,1H) 1.25 (m, 2H).

Example 31(1S,6R,7R/1R,6S,7S)-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E31)

To a stirred solution of 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylateand 1,1-dimethylethyl4-(3,4-dichlorophenyl)-6-[2-(methyloxy)ethyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(P56, mg) in dry DCM (4 mL) trifluoroacetic acid (0.75 ml) was added.The mixture was stirred at room temperature for 2 h, then the solventwas removed under reduced pressure and the crude purified by flashchromatography (eluting with DCM:MeOH: NH₃aq=95:5:0.5) to give 10 mg ofa mixture containing the title compound. MS (m/z): 286 [MH]⁺(1S,6R,7R/1R,6S,7S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(3.5 mg) was purified and separated from4-(3,4-dichlorophenyl)-6-[2-(methyloxy)ethyl]-1,2,3,6-tetrahydropyridineby semi-preparative HPLC using a chiral column Chiralpak AS-H, eluent A:n-hexane; B: ethanol, gradient isocratic 30% B, flow rate 0.8 ml/min,detection UV at 225 nm.

NMR (¹H, CDCl₃): δ 7.37 (d, 1H) 7.33 (d, 1H) 7.13 (dd, 1H) 4.01 (dd, 1H)3.78 (dd, 1H) 3.44 (s, 3H) 3.28-3.36 (m, 1H) 3.12-3.23 (m, 1H) 2.79-2.89(m, 1H) 2.52-2.65 (m, 1H) 1.96-2.12 (m, 1H) 1.80-1.96 (m, 1H) 1.28-1.47(m, 2H); MS (m/z): 286 [MH]+

Example 32(1S,6R,1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E32)

Method A:

The title compound may be obtained according to an analogous procedureto that described above for compound E2a in Method B, starting from1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P59).

Method B:

In a round-bottomed flask, 1,1-dimethylethyl(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate(P66, 42.33 g, 110 mmol) was dissolved in DCM (450 ml) to give acolourless solution. Trifluoroacetic acid (103 ml, 1343 mmol) was addeddropwise keeping the internal temperature below +5° C. with an ice bath.At the end of the addition, the ice bath was removed and the mixture wasstirred at room temperature for 2 hrs.

The reaction was quenched by dropwise addition of aqueous potassiumcarbonate sat. (250 ml) keeping the internal temperature below +10° C.with an ice bath. Then the mixture was diluted with water (200 ml) andDCM (200 ml). The two phases were separated. The aqueous phase wasextracted with ethyl acetate (2×150 ml) and the organic (milky solution)was evaporated under vacuum and taken up with ethyl acetate (400 ml).

The combined organics were washed with brine (300 ml), dried (Na₂SO₄)and evaporated under vacuum to obtain a yellow oil (34 g). It wasdissolved in diethyl ether (600 ml) and washed with aqueous potassiumcarbonate 1M solution (3×200 ml). The organic phase was dried (Na₂SO₄)and evaporated under vacuum to afford the title compound (28.9 g) ascolourless oil.

NMR (¹H, CDCl₃): δ ppm 7.45 (s, 1H), 7.36 (d, 1H), 7.19 (d, 1H), 3.32(d, 1H), 3.14 (s, 3H), 3.09 (d, 1H), 2.96 (d, 1H), 2.84 (d, 1H),2.73-2.81 (m, 1H), 2.64-2.71 (m, 1H), 1.92-2.00 (m, 1H), 1.79-1.88 (m,1H), 0.97-1.07 (m, 2H).

HPLC (walk-up): Rt=3.97 min

Example 33(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(2R,3R)-2,3-dihydroxybutanedioate (L-tartrate salt) (E33)

Method a)

3.7 grams of material prepared by a procedure analogous to the method ofStep A of Example 38, omitting the azeotropic drying step, was dissolvedin isopropyl alcohol (60 ml, 16.7 vols), and to the solution was addedL-tartaric acid [(2R,3R)-(+)-Tartaric acid](2.7 grams, 18.1 mmol, 1.4eq) and the solution was then heated to 80° C. Once at temperature water(12 ml, 3.2 vols) was then added and the solution stirred for 10 min.The resulting solution was then cooled to 0° C. at a rate of 0.2°C./min, and then held at 0° C. for 7 hours. The resulting slurry wasthen filtered and washed with isopropyl alcohol (10 ml, 2.7 vol) twice.The solid obtained was then dried under high vacuum for 5 hours at 50°C. to give an off white solid of the title compound (3.7 grams, 8.5mmol, 65% recovery).

NMR (¹H, DMSO-d6): δ ppm 1.22 (s, 2H), 2.03 (t, J=5.26 Hz, 2H),2.67-2.79 (m, 2H), 2.83-2.90 (m, 1H), 3.04 (s, 4H), 3.11 (d, J=13.19 Hz,1H), 3.43 (d, J=13.55 Hz, 1H), 3.85 (s, 2H), 7.33-7.39 (m, 1H),7.56-7.60 (m, 1H), 7.68 (d, J=2.01 Hz, 1H).

MS (m/z): 286 [MH]+

Method b)

To 300.1 mg of(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a) and 157.3 mg of L-tartaric acid, 0.5 mL of isopropylalcohol (IPA)was added with stirring. A further 0.5 mL was added and the resultingsolution heated using an air gun. Heat was removed and a further 2.5 mLIPA added, this resulted in a slurry to which an additional 1 mL of IPAwas added to give mobility (giving a total solvent volume of 4.5 mL IPAadded). The resulting slurry was temperature cycled between 0 and 40° C.for >24 hours. The sample was then filtered and the solid obtained driedunder vacuum at 70° C. for 24 hours.

Diffractogram of Form 1 of the title compound E33 [batch produced withmethod b)] is shown in FIG. 3.

XRPD Peaks* of Form 1 (with 5% or greater relative intensity) of thetitle compound Example 33 are illustrated in the Table 3 below (XRPDangles and d spacings are reported):

TABLE 3 Pos.[°2Th.]] d-spacing[Å] 4.8 18.3 9.5 9.3 11.7 7.6 13.1 6.813.6 6.5 15.5 5.7 15.9 5.6 16.9 5.2 17.2 5.2 17.5 5.1 17.9 4.9 18.8 4.723.5 3.8 23.9 3.7 24.5 3.6 24.9 3.6 26.3 3.4 26.5 3.4 26.9 3.3[X-Ray Powder Diffraction (XRPD) analysis performed on a PANalyticalX′pert Pro powder diffractometer, Model PW3040/60, serial number DY2599using an X′Celerator detector. Acquisition conditions: radiation: CuK_(α), generator tension: 40 kV, generator current: 40 mA, start angle:2.0 °2θ, end angle: 45.0 °2θ, step size: 0.017 °2θ, time per step:32.3024 seconds. Sample prepared using zero background (front fill)technique]

Onset of melting point/decomposition [E33, Form 1, batch produced withmethod b)]: 198° C. (TA instruments Q1000 serial number 01000-0577.Sample heated at 10° C. min⁻¹ in a crimped aluminium pan with a pin-holelid).

DSC thermogram of Form 1 of the title compound Example 33 [batchproduced with method b)] is shown in FIG. 4.

Method c)

To 500 mg of material prepared according to Step A of Example 38,dissolved in methanol (5 mL), was charged L-tartaric acid in methanol(1.21 mL, 1 mmol/mL). This was stirred for 15 minutes and a whiteprecipitate formed. This was collected by vacuum filtration and washedwith methanol (2 mL) to obtain 246 mg of title compound.

NMR (¹H, DMSO-d6): δ ppm 1.24 (s, 2H) 1.99-2.14 (m, 2H) 2.47-2.53 (m,1H) 2.67 (d, J=9.99 Hz, 1H) 2.72-2.83 (m, 1H) 2.92 (d, J=9.99 Hz, 1H)3.05 (s, 3H) 3.12 (d, J=13.20 Hz, 1H) 3.47 (d, J=13.38 Hz, 1H) 3.92 (s,2H) 7.39 (dd, J=8.34, 2.10 Hz, 1H) 7.59 (d, J=8.29 Hz, 1H) 7.70 (d,J=2.05 Hz, 1H)

Diffractogram of Form 1 of the title compound E33 is shown in FIG. 5.

XRPD Peaks* of Form 1 of the title compound E33 [batch produced withmethod c)] are illustrated in the Table 4 below (XRPD angles and dspacings are reported):

TABLE 4 2-theta [°] d-spacing [ ] 4.7 18.9 9.4 9.4 11.6 7.6 13.0 6.815.7 5.6 17.3 5.1 17.8 5.0 18.7 4.8 22.5 3.9 22.8 3.9 23.3 3.8 23.7 3.824.3 3.7 25.3 3.5 26.2 3.4 26.4 3.4 26.7 3.3 32.2 2.8 36.5 2.5 40.4 2.2*Values shown here are rounded to one decimal place. The diffractionpattern can shift to slightly higher or lower 2θ values depending onsample displacement.

[X Ray Powder Diffraction (XRPD) analysis was performed on a PANalyticalX'Pert-Pro MPD with Johansson Kal monochromator, using X'Celeratordetector. The acquisition conditions were as follows: Radiation: Cu(Kal), 1.540598 angstroms (monochromatic); Detector: X'Celerator;Tension: 45 kV; Current: 40 mA; Start angle: 2.0° 2q; End angle: 50.0°2q; Step size: 0.02°; Time/step: 40.0 sec; Scan speed: 0.05°/sec;Incident beam: 2° fixed anti-scatter slit, and programmable divergenceslit; Diffracted beam: 0.02 rad soller slit, and programmableanti-scatter slit; Samples prepared on silicon zero background sampleholder)].

In one embodiment, unique and discriminating peaks* of Form 1 of thetitle compound E33 have been identified and are illustrated in Table 5below (XRPD angles and d spacings are reported):

TABLE 5 2-theta [°] d-spacing [ ] 4.7 18.9 9.4 9.4 15.7 5.6 18.7 4.822.5 3.9 23.3 3.8 23.7 3.8 24.3 3.7 26.7 3.3 36.5 2.5

Onset of melting point/decomposition [E33, Form 1, batch produced withmethod c)]: 191.17° C. (TA Instruments Model 01000 DSC; Pan: closedaluminium; Purge gas: N₂, 50 mL/min; Temp range: 30-300° C., 15°C./min).

DSC thermogram of Form 1 of the title compound E33 [batch produced withmethod c)] is shown in FIG. 6.

The melt for Form 1 of the title compound E33 is followed by degradationtherefore the integration of the peak for different samples can giveslightly different Onset, Peak Max and Enthalpy values.

Examples 34 and 35 (2R,3R)-2,3-bis[(phenylcarbonyl)oxy]butanedioicacid-(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E34) and (2S,3S)-2,3-bis[(phenylcarbonyl)oxy]butanedioicacid-(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E35)

Step a)

To a solution of(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E32, 61.5 g, 215 mmol) in acetone (300 ml), dibenzoyl-L-tartaric acid(115 g, 322 mmol), dissolved in acetone (622 ml), was added dropwiseduring 1 h. A solid precipitated and the mixture was stirred at roomtemperature for 2 h. The solid was filtered, washed with acetone (2×100ml) and dried under vacuum to give compound E34 (35.8 g).

Chiral HPLC (Column: AS-H (25×0.46 cm), 5 micron; Eluent:n-Hexane/(2-propanol+0.1 isopropylamine) 95/5 v/v; Flow: 1 ml/min;wavelength: 225 nm; retention times referred to salt analysis): Enant1(Rt=12.14 min)/Enant2 (Rt=17.29 min)=86/13 area %

Mother liquors were concentrated under vacuum and the residue wassuspended in DCM (700 ml). It was washed with aqueous potassiumcarbonate sat./water 1:1 (700 ml). The aqueous phase was back-extractedwith DCM (2×500 ml). The collected organic phases, dried (Na₂SO₄), wereevaporated to give residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(45 g).

NMR (¹H, CDCl₃): δ ppm 7.45 (s, 1H), 7.36 (d, 1H), 7.19 (d, 1H), 3.32(d, 1H), 3.14 (s, 3H), 3.09 (d, 1H), 2.96 (d, 1H), 2.84 (d, 1H),2.73-2.81 (m, 1H), 2.64-2.71 (m, 1H), 1.92-2.00 (m, 1H), 1.79-1.88 (m,1H), 0.97-1.07 (m, 2H).

Chiral HPLC: (Column: AS-H (25×0.46 cm), 5 micron; Eluent:n-Hexane/(2-propanol+0.1 isopropylamine) 95/5 v/v; Flow: 1 ml/min;wavelength: 225 nm; retention times referred to free base):Enant1/Enant2=34/62 area %

Step b)

To residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(45 g, 157 mmol), coming from step a), dissolved in acetone (220 ml),dibenzoyl-D-tartaric acid (85 g, 236 mmol), dissolved in acetone (450ml), was added dropwise during 45 min. A solid precipitated and theresulting mixture was stirred at room temperature for 2 h. The solid wasfiltered, washed with acetone (2×100 ml) and dried under vacuum to givecompound E35 (43.89).

Chiral HPLC: Enant1/Enant2=7.5/90.9 area % Mother liquors wereconcentrated under vacuum and the residue was suspended in DCM (700 ml).

It was washed with aqueous potassium carbonate sat./water 1:1 (700 ml).The aqueous phase was back-extracted with DCM (2×500 ml). The collectedorganic phases, dried (Na₂SO₄), were evaporated to give residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(25.6 g).

Chiral HPLC: Enant1/Enant2=54/35 area %

Step c)

To residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(25.6 g, 89 mmol), coming from step b), dissolved in acetone (125 ml),dibenzoyl-L-tartaric acid (48.1 g, 134 mmol), dissolved in acetone (250ml), was added dropwise during 1 h. A solid precipitated and theresulting mixture was stirred at room temperature for 2 hrs. The solidwas filtered, washed with acetone (2×100 ml) and dried under vacuum toafford the compound E34 (15 g).

Chiral HPLC: Enant1/Enant2=92.5/5.5 area %

Mother liquors were concentrated under vacuum and the residue wassuspended in DCM (350 ml). It was washed with aqueous potassiumcarbonate sat./water 1:1 (350 ml). The aqueous phase was back-extractedwith DCM (2×300 ml). The collected organic phases, dried (Na₂SO₄), wereevaporated to give residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(18 g).

Chiral HPLC: Enant1/Enant2=37.7/49.7 area %

Step d)

To residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(18 g, 62.89 mmol), coming from step c), dissolved in acetone (90 ml),dibenzoyl-D-tartaric acid (33.8 g, 94.33 mmol), dissolved in acetone(180 ml), was added dropwise during 45 min. A solid precipitated and theresulting mixture was stirred at room temperature for 2 h. The solid wasfiltered, washed with acetone (2×80 ml) and dried under vacuum to givecompound E35 (11 g).

Chiral HPLC: Enant1/Enant2=14.5/84.5 area %

Mother liquors were concentrated under vacuum and the residue wassuspended in DCM (500 ml).

It was washed with aqueous potassium carbonate sat./water 1:1 (500 ml).The aqueous phase was back-extracted with DCM (2×300 ml). The collectedorganic phases, dried (Na₂SO₄), were evaporated to give residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(12.6 g).

Chiral HPLC: Enant1/Enant2=49.2/31.2 area % Step e)

To residual6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(12.6 g, 44 mmol), coming from step d), dissolved in acetone (65 ml),dibenzoyl-L-tartaric acid (23.66 g, 66 mmol), dissolved in acetone (125ml), was added dropwise during 1 h. A solid precipitated and theresulting mixture was stirred at room temperature for 2 hrs. The solidwas filtered, washed with acetone (2×100 ml) and dried under vacuum toafford compound E34 (3.1 g). 10.57% yield.

Chiral HPLC: Enant1/Enant2=94.1/5.0 area %

Step f) (2R,3R)-2,3-bis[(phenylcarbonyl)oxy]butanedioicacid-(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E34) coming from step a) (35.8 g, 55.54 mmol), step c) (15 g, 23.27mmol), step e) (3.1 g 4.8 mmol) and a further batch of material (3.1 g,4.8 mmol) of the same quality were suspended in acetone (570 ml) andheated gently to reflux for 30 min. The mixture was stirred for 2 hrs atroom temperature. The solid was filtered to give 47.25 g of white solid.This solid was suspended in acetone (470 ml) and heated to reflux for 30min. The mixture was stirred for 2 h at room temperature. The solid wasfiltered to give 41.80 g of white solid. This solid was suspended inacetone (420 ml) and heated to reflux for 30 min. The mixture wasstirred for 2 h at room temperature The solid was filtered to give purecompound E34 (38 g) as white solid.

NMR (¹H, MeOH-d₄): δ ppm 8.14 (d, 4H), 7.57-7.67 (m, 3H), 7.41-7.54 (m,5H), 7.29-7.38 (m, 1H), 5.93 (s, 2H), 3.61-3.76 (m, 1H), 3.16-3.29 (m,2H), 3.13 (s, 3H), 2.98-3.07 (m, 1H), 2.79-2.92 (m, 1H), 2.66-2.78 (m,1H), 2.08-2.29 (m, 2H), 1.12-1.31 (m, 2H)

Chiral HPLC: Enant1/Enant2=99/1 area %

Example 36(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanebutanedioate (Mono-Succinate salt) (E36)

To 300.7 mg of(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a) and 123.4 mg of succinic acid, 0.5 mL of isopropylalcohol (IPA)was added with stirring. A further 0.5 mL was added and heat appliedusing an air gun to aid dissolution. Further solvent additions of 2×0.5mL, 1 mL, 0.5 mL and 1 mL were added to achieve a mobile slurry (givinga total solvent volume of 4.5 mL IPA added). The resulting slurry wastemperature cycled between 0 and 40° C. for three days. The sample wasthen filtered and the solid title compound obtained dried under vacuumat 70° C. for 24 hours.

NMR (¹H, DMSO-d6): 7.67 (d, 1H), 7.59 (d, 1H), 7.36 (dd, 1H), 3.40 (d,1H), 3.09 (d, 1H), 3.05 (s, 3H), 3.01 (m, 1H), 2.87 (d, 1H), 2.77-2.70(m, 2H), 2.34 (s, 4H), 2.01 (m, 2H), 1.21 (m, 2H) [NMR analysisperformed on a batch obtained with an analogous procedure to that abovedescribed]

Example 37(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanephosphate (monophosphate salt) (E37)

A solution was prepared with 301.5 mg(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane(E2a, oil) and 0.2 mL aqueous isopropylalcohol 5% w/w water (aq. IPA).To this solution 209.6 microL of phosphoric acid (5M in water) was addedwith stirring. A further 0.1 mL of solvent was added while stirringyielding a slurry. 0.3 mL and then 00.1 mL of solvent were added to givea mobile slurry. (Total aq. IPA added 0.7 mL). The resulting slurry wastemperature cycled between 0 and 40° C. for 24 hours. The sample wasthen filtered and the solid title compound obtained dried under vacuumat 70° C. for 24 hours.

The analytical data reported below for E37 were generated usingalternative batches of the compound.

NMR (¹H, DMSO-d6): 7.63 (d, 1H), 7.56 (d, 1H), 7.36 (dd, 1H), 7.27 (d,1H), 3.03 (s, 3H), 3.01 (d, 1H), 2.90 (d, 1H), 2.85 (m, 1H), 2.69 (d,1H), 2.64 (m, 1H), 1.95 (m, 2H), 1.17 (m, 2H)

Diffractogram of Form 1 of the title compound E37 is shown in FIG. 7.

XRPD Peaks* of Form 1 (with 5% or greater relative intensity) of thetitle compound Example 37 are illustrated in the Table 6 below (XRPDangles and d spacings are reported):

Pos.[°2Th.] d-spacing[Å] 5.1 17.4 10.2 8.7 12.0 7.3 13.3 6.7 16.8 5.318.5 4.8 18.9 4.7 19.9 4.5 20.4 4.4 21.2 4.2 22.0 4.0 22.5 4.0 23.2 3.824.0 3.7 25.3 3.5 25.7 3.5 26.6 3.4 27.5 3.2 28.4 3.1 29.6 3.0 30.8 2.9[X-Ray Powder Diffraction analysis performed on a PANalytical X₁ pertPro powder diffractometer, Model PW3040/60, serial number DY2599 usingan X₁Celerator detector. Acquisition conditions: radiation: Cu K_(α),generator tension: 40 kV, generator current: 40 mA, start angle: 2.0°2θ, end angle: 45.0 °2θ, step size: 0.017 °2θ, time per step: 32.3024seconds. Sample prepared using zero background (front fill) technique.).

DSC thermogram of Form 1 of the title compound E37 is shown in FIG. 8.

Onset of melting (E37, Form 1): 199° C. (TA instruments Q1000 serialnumber Q1000-0577. The sample was heated at 10° C. min⁻¹ in a crimpedaluminium pan with a pin-hole lid).

The melt for Form 1 of the title compound E37 is followed by degradationtherefore the integration of the peak for different samples can giveslightly different Onset, Peak Max and Enthalpy values.

Example 38(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanetrifluoroacetate (ratio Ion:counterion not determined) (E38)

Step A:

1,1-dimethylethyl(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]hept-4-ene-3-carboxylate(P60, 11 g) was dissolved in toluene (110 ml). The solution was treatedwith triethylsilane (5.46 ml, 34.17 mmol), followed by trifluoroaceticacid (14.81 ml, 199.3 mmol). The reaction was stirred at roomtemperature for 24 h, then quenched with sodium hydroxide and stirredfor 10 min. The pH of the mixture was approximately 13. The phases wereseparated and the toluene phase concentrated in vacuo to give a productintermediate as an oil, which was further dried by performance of threeazeotropes.

Step B, Method A:

3 g of the material produced in step A were dissolved in ethyl acetateand heptane was added until the solution became cloudy. The solution washeated until dissolution and then allowed to cool. Crystals' formationwas observed. The solid was then filtered and 1 g of title compound wasrecovered.

Step B, Method B:

6 g of the material produced in Step A were dissolved in 12 mL of ethylacetate. Heptane (60 mL) was added to this solution and the biphasicmixture was then heated to −70° C. to obtain a single phase solution. Tothis solution another portion of heptane (60 mL) was added and thesolution heated to reflux (90° C.). The solution was then allowed tocool while stirring to 67° C., at which temperature it was seeded withcrystals of the title compound previously obtained as described in StepB, Method A. The solution was then allowed to cool to room temperatureovernight.

The resulting precipitate was then filtered by vacuum filtration andwashed with heptane (5 mL). Title compound was obtained (1.5 g) as acrystalline solid (25% recovery)

NMR (¹H, CDCl₃): δ ppm 1.23 (dd, 2H) 2.16-2.25 (m, 1H) 2.31-2.43 (m, 1H)2.84 (d, J=9.99 Hz, 1H) 2.92-2.97 (m, 1H) 3.15 (s, 3H) 3.18-3.28 (m, 2H)3.76 (d, J=13.20 Hz, 1H) 7.34-7.39 (m, 1H) 7.40-7.43 (m, 1H) 7.51 (d,J=1.96 Hz, 1H) 9.65 (s, 1H)

Diffractogram of Form 1 of the title compound E38 is reported in FIG. 1.Peaks* of Form 1 of the title compound Example 38 are illustrated in theTable 1 below (XRPD angles and d spacings are reported):

TABLE 1 2-theta [°] d-spacing [ ] 5.1 17.3 10.0 8.8 10.2 8.6 10.6 8.315.4 5.7 18.6 4.8 19.3 4.6 20.6 4.3 21.0 4.2 21.4 4.1 22.2 4.0 23.3 3.823.5 3.8 25.5 3.5 25.9 3.4 26.0 3.4 30.4 2.9 31.2 2.9 35.5 2.5 39.5 2.3*Values shown here are rounded to one decimal place. The diffractionpattern can shift to slightly higher or lower 2θ values depending onsample displacement.

[X Ray Powder Diffraction (XRPD) analysis was performed on a PANalyticalX'Pert-Pro MPD with Johansson Kal monochromator, using X'Celeratordetector. The acquisition conditions were as follows: Radiation: Cu(Kal), 1.540598 angstroms (monochromatic); Detector: X'Celerator;Tension: 45 kV; Current: 40 mA; Start angle: 2.0° 2q; End angle: 50.0°2q; Step size: 0.02°; Time/step: 40.0 sec; Scan speed: 0.05°/sec;Incident beam: 2° fixed anti-scatter slit, and programmable divergenceslit; Diffracted beam: 0.02 rad soller slit, and programmableanti-scatter slit; Samples prepared on silicon zero background sampleholder)].

In one embodiment, unique and discriminating peaks* of Form 1 of thetitle compound Example 38 have been identified and are illustrated inTable 2 below (XRPD angles and d spacings are reported):

TABLE 2 2-theta [°] d-spacing [ ] 5.1 17.3 10.2 8.6 10.6 8.3 15.4 5.718.6 4.8 19.3 4.6 21.4 4.1 22.2 4.0

Onset of melting (E38, Form 1): 123.91° C. (TA Instruments Model Q100DSC; Pan:closed aluminium; Purge gas: N₂, 40 mL/min; Temp range: 30-300°C., 15° C./min). DSC thermogram of Form 1 of the title compound Example38 is shown in FIG. 2.

It is to be understood that the present invention covers allcombinations of particular groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims.

1. A pharmaceutical composition comprising a compound of formula (A)′ ora pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R₁ is hydrogen or C₁₋₄alkyl; R₂ is a group A, K or W wherein Ais

K is an α or β naphthyl group, optionally substituted by 1 or 2 groupsR₁₈, each of them being the same or different; and W is

and wherein G is a 5- or 6-membered monocyclic heteroaryl group, or a 8-to 1′-membered heteroaryl bicyclic group; wherein G may be substitutedby (R₁₅)_(p), which can be the same or different; p is an integer from 0to 5; R₃ is selected from the group consisting of: hydrogen, fluorine,and C₁₋₄ alkyl; or corresponds to a group X or X₁; R₄ is selected fromthe group consisting of: hydrogen, fluorine, and C₁₋₄ alkyl; orcorresponds to a group X or X₁; R₅ is hydrogen or C₁₋₄ alkyl; R₇ ishydrogen or C₁₋₄ alkyl; or is a group X, X₁, X₂ or X₃; wherein X is

X₁ is

X₂ is

and X₃ is

R₆ is hydrogen or C₁₋₄ alkyl; or is a group X or X₁; R₉ is C₁₋₄alkyl;R₁₀ is selected from the group consisting of: hydrogen, halogen,hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₈ is a 5-6 memberedheterocycle group, which may be substituted by one or two substituentsselected from the group consisting of: halogen, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl; R₁₁ is selected from thegroup consisting of: hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; orcorresponds to a group R₈; R₁₂ is selected from the group consisting of:hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₁₃is selected from the group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₁₄ is selected fromthe group consisting of: hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; orcorresponds to a group R₈; R₁₅ is selected from the group consisting of:halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₁₆is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₃alkyl; R₁₇is hydrogen or C₁₋₄alkyl; R₁₈ is selected from the group consisting of:halogen, cyano, and C₁₋₄alkyl; R₁₉ is haloC₁₋₂alkyl; and n is 1 or 2;and a pharmaceutically acceptable carrier.
 2. A compound of formula (I)′or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein is hydrogen or C₁₋₄ alkyl; is a group A, K or W wherein A is

K is an α or β naphthyl group, optionally substituted by 1 or 2 groupsR₁₈, each of them being the same or different; and W is

and wherein G is a 5,6-membered monocyclic heteroaryl group, or a 8- to1′-membered heteroaryl bicyclic group; wherein G may be substituted by(R₁₅)_(p), which can be the same or different; p is an integer from 0 to5; R₃ is selected from the group consisting of: hydrogen, fluorine, andC₁₋₄ alkyl; or corresponds to a group X or X₁; R₄ is selected from thegroup consisting of: hydrogen, fluorine, and C₁₋₄ alkyl; or correspondsto a group X or X₁; R₅ is hydrogen or C₁₋₄ alkyl; R₇ is hydrogen or C₁₋₄alkyl; or is a group X, X₁, X₂ or X₃; wherein X is

X₁ is

X₂ is

and X₃ is

R₆ is hydrogen or C₁₋₄ alkyl; or is a group X or X₁; R₉ is C₁₋₄alkyl;R₁₀ is selected from the group consisting of: hydrogen, halogen,hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₈ is a 5-6 memberedheterocycle group, which may be substituted by one or two substituentsselected from the group consisting of: halogen, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy and C₁₋₄alkanoyl; R₁₁ is selected from thegroup consisting of: hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; orcorresponds to a group R₈; R₁₂ is selected from the group consisting of:hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₁₃is selected from the group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy,C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₁₄ is selected fromthe group consisting of: hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; orcorresponds to a group R₈; R₁₅ is selected from the group consisting of:halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds to a group R₈; R₁₆is hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkylC₁₋₃alkyl; R₁₇is hydrogen or C₁₋₄alkyl; R₁₈ is selected from the group consisting of:halogen, cyano, and C₁₋₄alkyl; R₁₉ is haloC₁₋₂alkyl; and n is 1 or 2;with the proviso that: if R₂ is A, R₃, R₄, R₅, R₆, R₇, R₁₀, R₁₁, R₁₃,and R₁₄ are hydrogen, and R₁₂ is fluorine, R₁ is C₁₋₄ alkyl; if R₂ is A,R₃, R₄, R₅, R₆, R₇, R₁₀, R₁₁, R₁₃, and R₁₄ are hydrogen, and R₁ ismethyl, R₁₂ is halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl or SF₅; or corresponds to agroup R₈.
 3. A compound as claimed in claim 2, which is a compound offormula (IC)

wherein R₁, R₂, R₇ and R₁₇ are as defined for compounds of formula (I)′,or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 4. Acompound as claimed in claim 2, which is a compound of formula (ID)

wherein R₂, R₁₆ and n are as defined for compounds of formula (I)′, or apharmaceutically acceptable salt, solvate or prodrug thereof.
 5. Acompound of Formula (ID) according to claim 4, wherein n is
 1. 6. Acompound as claimed in claim 2, which is a stereochemical isomer, havinga single absolute configuration at stereogenic centers named 1 and 6, offormula (I)″

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₁₇ are as defined as above forcompounds of formula (I)′, or a pharmaceutically acceptable salt,solvate or prodrug thereof.
 7. A compound of formula (I)′, as claimed inclaim 2, selected from the group consisting of:(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo-[4.1.0]heptane;(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;[(1S,6R/1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;[(1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;[(1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]hept-1-yl]methanol;(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;(1R,6S)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane;(1S,6R)-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane; (1R,4S,6S/1S,4R,6R)-6-(3,4-dichlorophenyl)-4-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1S,6R)-6-(3,4-dichlorophenyl)-3-methyl-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S/1S,6R)-6-[4-chloro-3-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S/1S,6R)-6-(4-chlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S or1S,6R)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1S,6R or1R,6S)-6-(3,4-dichlorophenyl)-1-[(ethyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1S,6R/1R,6S)-[(methyloxy)methyl]-6-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[4.1.0]heptane;(1S,6R/1R,6S)-6-[3-chloro-4-(trifluoromethyl)phenyl]-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S/1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;(1R,6S or1S,6R)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;(1S,6R or1R,6S)-1-[(methyloxy)methyl]-6-(2-naphthalenyl)-3-azabicyclo[4.1.0]heptane;(1S,6R/1R,6S)-6-(3-chloro-4-fluorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;(1R,6S/1S,6R)-6-(3,4-dichlorophenyl)-1-{[(2,2,2-trifluoroethyl)oxy]methyl}-3-azabicyclo[4.1.0]heptane;and (1S,6R,7R/1R, 6S,7S)-6-(3,4-dichlorophenyl)-7-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 8. Acompound of formula (I)′, as claimed in claim 2, which is(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane;or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 9. Amethod of treating a condition for which inhibition of serotonin (5-HT),dopamine (DA) and norepinephrine (NE), is beneficial, which comprisesadministering to a human in need thereof an effective amount of acompound of claim 2, or a pharmaceutically acceptable salt, solvate orprodrug thereof.
 10. A method as claimed in claim 9, wherein thecondition to be treated is depression. 11-15. (canceled)
 16. A method oftreating a condition for which inhibition of serotonin (5-HT), dopamine(DA) and norepinephrine (NE), is beneficial, which comprisesadministering to a human in need thereof an effective amount of acompound of formula (A)′ as described in claim 1 or a pharmaceuticallyacceptable salt, solvate or prodrug thereof.
 17. A method as claimed inclaim 16, wherein the condition to be treated is depression. 18-21.(canceled)
 22. A pharmaceutical composition comprising a compound asclaimed in claim 2, or a pharmaceutically acceptable salt, solvate orprodrug thereof and a pharmaceutically acceptable carrier.
 23. A methodof treating a condition for which inhibition of serotonin (5-HT),dopamine (DA) and norepinephrine (NE), is beneficial, which comprisesadministering to a human in need thereof an effective amount of acompound of claim 7, or a pharmaceutically acceptable salt, solvate orprodrug thereof.
 24. A method as claimed in claim 23, wherein thecondition to be treated is depression.
 25. A pharmaceutical compositioncomprising a compound as claimed in claim 7, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof and a pharmaceuticallyacceptable carrier.